NeuroscienceandBiobehavioral Reviews, Vol. 16, pp. 399--413, 1992

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Thermal Influences on N e r v o u s System Function 1 RAELYN

JANSSEN

N e u r o p h y s i o l o g i c a l T o x i c o l o g y Branch, N e u r o t o x i c o l o g y Division, U.S. E n v i r o n m e n t a l P r o t e c t i o n A g e n c y , Research Triangle Park, N C 27711

R e c e i v e d 15 J u l y 1991 JANSSEN, RAELYN. Thermal influences on nervous system function. NEUROSCI BIOBEHAV REV 16(3) 399-413, 1992.-The various effects of temperature change are only partially predictable. Temporal measures relevant to membrane activity, action potentials, synaptic transmission, and evoked potentials are all consistently increased with cooling and decreased by warming. However, the various measures of amplitude at different levels, and even within similar preparations, are contradictory: Some laboratories report increased amplitudes with cooling and others report decreased amplitudes under similar conditions. Emphasis is given to identifying factors that may resolve the differences. These include: (a) the rate of temperature change, (b) sites of cooling, stimulation and recording, (c) stimulus characteristics, and (d) fundamental differences in temperature sensitivities of different neural tissue. Other factors that may affect the ability to predict thermal influences on neural function from existing formulations are: relative ion permeabilities, metabolic ion pumps, the resting potential at the onset of cooling, and an animal's acclimated temperature at sacrifice. Temperature Nervous system Neurophysiology

Hypothermia

Cooling

Qt0

Hyperthermia

Neuron

is lowered. The relationship between temperature and the rate of chemical reactions in general is described by the Arrhenius equation:

T H E functional characteristics of the nervous system are influenced by temperature. For this reason, temperature often has been manipulated in order to study the operation of the nervous system and to characterize its basic properties. The impetus for this review was the contradictory reports of thermal effects on sensory evoked potentials, specifically evoked potential amplitudes; some papers report increased amplitudes, and others report decreased amplitudes under hypothermic conditions. The goal of this review is to integrate what is known about the various effects of temperature and temperature change on neural function, beginning at the subcellular and cellular level and ending with complex multisynaptic systems. In the process, information is gathered that will be applied to the amplitude issue. A glossary of terms used in thermal physiology has been compiled by the Commission for Thermal Physiology of the International Union of Physiological Sciences (72). The material presented in the body of this review is mostly electrophysiological in nature. The appendix summarizes some general effects of temperature that usually are not measured electrophysiologically, i.e. metabolic effects, effects on bloodbrain barrier, susceptibility to insult, and axonal transport. Purely physicochemical relationships underlie the temperature-dependence of biological activity. For example, enzymecatalyzed reactions occur at a reduced rate when temperature

KT2 = KT, • e-~/RItT2- TI)/TzTI' in which K is a rate constant, expressing frequency of molecular collision, T is absolute temperature in Kelvin,/~ represents activation energy, and R is the universal gas constant (6,143). Thus, the rate constant of a chemical reaction is related to temperature in an exponential way, with events occurring more slowly as temperature is reduced. Small changes in temperature result in large changes in reaction velocity. If the temperature of a homeothermic animal were to fall from 37 ° C, for example, to 0 ° C, the metabolic rate would drop approximately 16-fold (105). In one-celled animals, the rate of protein synthesis doubles between 18 and 27 ° C (128). This exponential relationship is the basis of the importance of maintaining body temperatures within a narrow range (105). The traditional expression of temperature-dependent relationships is the temperature coefficient, Q~0: the ratio of the rate of a process at one temperature to its rate at a temperature 10 ° C lower (62,118). When applied in a physiological context, the values used in the ratio may be any sort of data, e.g., latencies or amplitudes rather than rates (62,70). Sometimes

This paper has been reviewed by the United States Environmental Protection Agency, and approved for publication. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. 399

400

JANSSEN

the inverse of temperature coefficients are reported, i.e., the ratio of the lower temperature's value to the value at the higher temperature, or 1/Q~ o, in order that the Q~0s be greater than I (70). The effect of temperature is more readily appreciated when a value is expressed as being, for example, 3 or 4 times another value (Qi0 = 3 or 4) than when their ratio (Qi0) is 0.33 or 0.25. In this review, the Q~0s reported will usually be the ratio of the value at the higher temperature to the value at the lower in order to keep clear the direction of effects. Thus, if duration or amplitude is greater at lower temperatures, the reported Q~os will be less than 1, whether the data come from cooled or warmed tissue. Occasionally, to emphasize a point or to compare measures, inverted Q~oswill be used and explicitly noted. In these cases, "iQ~0" will symbolize the inversion of the QJo values. Where Q~osare not specifically reported in the source material, they can sometimes be approximated from the published data, and these approximations are presented. Biological Q~0 values greater than 2 are generally considered indicative of processes that use metabolic energy (15,86). The temperature coefficients of a number of purely physical and physicochemical processes have been used to predict the effect of temperature on some physiological processes. There is close correspondence between predicted temperature coefficients and those reported in the literature for a wide range of data on nerve and muscle activity (126). T H E R M A L EFFECTS IN NONSYNAPTIC PREPARATIONS

Membrane Properties: Resting Membrane Potential and Membrane Resistance

Temperature is a determinant of the resting potential across the nerve cell membrane. The Nernst equation predicts resting membrane potential from ion concentrations: E = R___TIn [K]o + [Na]o + [Cl]i F [K]i + [Na]i + [Cl]o ' where R and T have the same meanings as in the Arrhenius equation, F is the Faraday constant indicating the electric charge per gram equivalent of univalent ions, and [ ]~ and [ ]o indicate concentrations of specific ions inside and outside the cell. Resting potential is also predicted by the GoldmanHodgkin-Katz equation, which includes ion permeability as an additional factor: E = R T In PK[K]o + PNa[Na]o + Pcl[COi F Pr[K]i + Pna[Na]i + Pet[el] o '

where Px stands for permeability to a specific ion (50,65). Both equations predict that decreases in temperature will depolarize the cell membrane. They assume both that the ratio of sodium permeability to potassium permeability does not vary with temperature, and that active (metabolic) processes do not contribute to the membrane potential. These equations predict well, but in some experiments reported by Gorman and Marmor they are improved by consideration of metabolic and permeability factors, which appear to be temperature-sensitive (54,55). The hyperpolarization observed in an in vitro molluscan ganglion cell preparation while warming it from 7 to 17 ° C (20 mV, Q~0 approximately 1.4) is greater than that predicted by either equation (54). The discrepancy has been attributed to the operation of an active metabolic ion pump. Further, the ion pump's contribution to membrane potential may depend on the time course of temperature treatment. Holding a cell at temperatures below

5 ° C for 15 to 60 minutes can bring about an enhancement of hyperpolarization in response to warming. This has been attributed to stimulation of pump activity by the accumulation of sodium ions inside the cell (54). In these studies, alterations in temperature also alter membrane permeability relationships. The ratio of sodium permeability to potassium permeability, assumed to be constant in the Goldman-Hodgkin-Katz and Nernst equations, more than doubles over the range of 4 to 18" C in the molluscan ceil. An increase in sodium permeability is probably the dominant factor in this change (55). The importance of the electrogenic sodium-potassium pump in contributing to resting membrane potential in these experiments seems to contradict other findings. For example, using metabolic inhibitors to virtually eliminate pump activity in cephalopod axons produces no immediate effect on resting potential (66,67,68). Little effect of the pump is seen in mammalian neurons in vivo (86). This disagreement may be at least partially resolved by consideration of the temperature range and species used in the studies. In crabs, the rate of hydrolysis of ATP by the sodium-potassium-ATPase of the axonal membrane is different between 20 and 40 ° C than it is between 0 and 20" C (47). The temperature-related difference in metabolic rate may be the result of a structural transformation in the membrane lipids (47). The temperature at which the functional transition occurs may differ across species, and also may differ according to the temperature to which the experimental animal was acclimated. For example, in a giant neuron of the fresh water snail, Helis o m a trivolvis, the relationship of resting potential to temperature depends on the temperature to which the animal had been acclimated (102). The difference due to acclimation is attributed to activity of the sodium ion pump because it disappears in the presence of ouabain (102). The altered pump activity occurs over an acclimation period of about a month, and is considered to be a compensatory mechanism which permits adjustment to changes in the resting potential which might occur over a 30 ° range of seasonal temperatures (102). It is likely that the mechanism of this adjustment of the sodium ion pump involves an alteration of the membrane resistance across which a constant current is generated, rather than a change in the current itself (102). Another factor relevant to the importance of the metabolic ion pump in determining resting membrane potential is the relatively greater contribution of the pump at the soma than at the axon (102). Differences due to acclimation temperature have also been observed with respect to another facet of neural function, i.e., sodium channel activation, which will be discussed in the section on action potentials. A change in sodium channel activation characteristics occurs at temperatures below 10 ° C, and the transition temperature is lower in frogs living in a cooler climate (123). The difference may be due to a temperature-induced structural transformation in the lipids surrounding the sodium channel proteins (123). The traditional formulations, besides simplifying the temperature responses with respect to permeability and active metabolism, omit the role of calcium ions and membrane transport mechanisms in the neuronal soma. These transport mechanisms include sodium-calcium exchange, carriermediated passive diffusion, and calcium-magnesium-ATPase, all of which may be sensitive to temperature. The array of active and passive membrane transport systems that contribute to resting membrane potential forms a basis for cellular diversity in response to temperature because they are present in different combinations in different cell types (124). Despite such cell-type diversity, the depolarization re-

THERMAL INFLUENCES ON NEURAL FUNCTION sponse to cooling that is predicted by these equations has been reported consistently across a variety of preparations. It is observed in bifurcated axons of crustacean motor neuron with a pattern of results very similar to those of Gorman and Marmor over the same temperature range (58). Depolarization is also seen in cat spinal motoneurons in vivo at temperatures between 40 and 30 ° C (86,110), and it occurs even within a small range (4 ° C) of axonal temperatures in this preparation (110). An attempt to determine the effect of cooling on the sodium ion pump in the cat spinal preparation failed to distinguish between temperature effects on the pump and those on the sodium-potassium permeability ratio (86), although the time course of the depolarization effect was not consistent with that of the permeability ratio change reported for molluscan cells (55). The in vivo preparation exhibits greater lability than the in vitro models (86), possibly the result of using rapid local cooling, to be discussed later. During the course of cooling and warming cells, resting membrane potential at intermediate temperatures (in vivo) depends on the direction of temperature change, in that, during rewarming a transient overshoot in hyperpolarization may be observed (86). Enhanced hyperpolarization in response to warming was also observed in Gorman and Marmor's (54) in vitro preparation when the cell had been held at a lower temperature. In addition, a cell's membrane potential in vivo may vary at the outset of repeated coolings and its response to each cooling depends on its voltage at the initial temperature. The change in potential is greater when the cell is cooled beginning at a lower potential (86). In other words, the more depolarized the cell is, the greater its depolarization will be when cooled. Membrane resistance is greater at lower temperatures, but the temperature coefficients depend somewhat on the preparation. Table 1 summarizes reported Q~0 values for input resistance. In the cat spinal preparation, where the animal is anesthetized with sodium pentobarbital and immobilized with gallamine triethiodide (Flaxedil), input resistance displays a more dramatic effect than in the in vitro preparations, doubling over the temperature range used. Note that in in vitro slices of guinea pig hippocampus, the input resistance for cells stabilized at 37 ° C then stabilized at 27 ° C is more affected than that for cells observed during the process of cooling. Increased membrane resistance, like depolarization, is appreciable within a small range of axonal temperatures in the cat spinal motoneuron (1 I0). But the time courses of the resting potential and resistance changes differ in cells cooled by about 4 ° and rewarmed to normal body temperature. Membrane resistance begins to increase 10 seconds after cooling begins and declines to control levels within 2 or 3 minutes after cooling stops. Depolarization in response to cooling begins about a minute after the onset of cooling and lasts for 20

401 minutes after rewarming (110). The lag time for resistance changes may explain the difference in Q~0 values of temperature-stablized and unstabilized hippocampal cells (136).

Characteristics of the Action Potential Excitability and conductivity. The excitability of a cell, or its tendency to produce an action potential, depends on changes in ion conductance. Propagation depends on both conductance changes and the cable properties of the cell, including membrane capacitance, the resistivities of cytoplasm and cell medium, and cellular geometry. Cable properties in turn influence excitability by affecting input impedance and response time (78). The temperature dependencies of both excitation and cable properties are predicted by the formulation of Hodgkin and Huxley (64). Joyner (78) compared these predictions with published experimental results on basic electrical parameters: membrane capacity, axoplasmic resistance, equilibrium potentials for sodium and potassium, maximum conductances for sodium and potassium, and rate constants. All the measurements reviewed were made on squid giant axon. Predicted and experimental Q~0s for this model are impressively close. Axoplasmic resistance (inverted Q~0s, or iQ~os = 1.2 to 1.3) and maximum ion conductances (Q~0 = 1.4) are the most temperature sensitive cable parameters, except for the rate constants, which were scaled by a Q~0 of 3 in the formulation (selected Q~0 = 3). The temperature dependence of axoplasmic resistance is roughly comparable to that of input resistance. The membrane potential at the threshold of firing is that potential at which the inward sodium current is equal to the outward potassium current (79). This equivalence may conceivably occur at a range of potential values that are themselves temperature-dependent. Thus, the depolarization that accompanies cooling may not necessarily place a cell closer to its firing threshold, because that threshold may change with temperature. Based on increased input resistance, a higher spike threshold would be expected in a cooled neuron. In fact, the data are not consistent on this point. According to Hille (62) and J. R. Schwarz (121), the ion permeability changes associated with the initiation of an action potential occur more slowly at low temperatures, requiring a greater charge in order to fire. An increased threshold for firing occurs in conjunction with cooling in crustacean axon (58), and in cat spinal cord in vivo (18). In single motor nerve fibers of the spring toad, a doubling of threshold has been reported in response to a 13degree temperature drop (134). On the other hand, the application of a subthreshold depolarizing current to a cat spinal cord cell in vivo that has been cooled by as little as 0.5 ° C almost always results in an action

TABLE 1 OBSERVED TEMPERATURECOEFFICIENTSFOR INPUT RESISTANCE Q~o

Temperature Range

Coolingor Warming

Preparation

Ref

0.49 0.63 0.76 0.58

40-30 ° C 5-10 ° C 10-15o C 37-27 o C (Stabilized) 37-27° C (In Flux)

Cooling Warming Warming Cooling

Cat spinal motoneuron Crustacean axon Crustacean axon Guinea pig hippocampal slice

(86) (58) (58) (I 36)

Cooling

Guinea pig hippocampal Slice

(136)

0.75

402 potential (110). Furthermore, cooling this preparation by up to 6* C renders the soma-dendritic membrane more excitable in response to the second of a pair of antidromic pulses (86). Below this temperature range, a spike generated at the initial segment fails to trigger a soma-dendritic spike although local responses sometimes occur (86). It thus appears that mild hypothermia can raise the probability that a second spike will propagate antidromically from the initial segment, and that cooling acts differentially on the behavior of the somadendritic region and the axon hillock in response to paired antidromic stimuli. It is unclear whether the discrepancy with respect to spike threshold is due to the differences in these preparations (cell body vs. axonal recording), or whether there is a discontinuity in the function describing the firing threshold-temperature relationship. Such a discontinuity may derive from the differential time course of resistance and depolarization changes discussed above, or may indicate an underlying U-shaped function. Temporal characteristics. Changes in the propagated action potential induced by cooling are large compared with resting potential changes, and the latter may not necessarily predict the former (65,86,103). The Hodgkin-Huxley predictions of action potential parameters compare well with published data on squid giant axon (78). Predicted Q~0s for amplitude, duration, net ionic movements, maximum rate of rise, and conduction velocity are strikingly similar. With the significant exception of amplitude, these predictions work well for other biological preparations. The ion channel activity that underlies the action potential is dramatically slowed when temperature is reduced. The Q~0s of ion permeability, channel activation and inactivation for sodium (11,45,76,84,115,121,122), potassium (45,75,115), and some calcium (1,19,24,53,87,93,106) ion channels range from about 1.5 to about 3, at temperatures above 10 ° C. Low-threshold calcium channels display a temperature sensitivity similar to that of sodium and potassium channels (106), but high-threshold calcium channels are markedly more sensitive to temperature (106). The Q~0s of high-threshold channel activation and inactivation are 5 and 3.5 respectively, whereas those for low-threshold calcium channels are 1.9 and 2.2 respectively (106). In vivo, stages of sodium and potassium ion activity may be inferred from components of the differentiated action potential (86). Thus represented, the maximum rates of successive sodium activation of the initial segment (axon hillock) and the soma-dendritic membrane, and the following sodium inactivation and potassium activation of the soma-dendritic compartment are all decreased when cooled. The potassium activation in the soma-dendritic portion of the cell is most affected, and sodium activation least affected, by cooling over a 7 ° range. These responses, which were recorded from anesthetized cat motoneuron, exhibit Qj0s ranging from 1.71 to 3.12 (86). These values agree with those cited above from studies of channel kinetics and permeability. Studies in which the temporal characteristics of the single unit action potential have been specifically measured give a consistent picture of slowed activity at reduced temperatures. With cooling, duration increases in a monotonic way (46, 48,58,65,86,119,134,136). The Q,0s of this relationship, where available, range from about 0.6 to 0.3 (inverted or iQios of 1.7 to 3.3), despite the wide variety of preparations and temperatures used. The increased duration reflects prolonged rise and decay phases of the action potential (46,58,89). The rate of fall is more affected than the rate of rise, often by a factor

JANSSEN of 2 or more (45,65,110,119,136). The hyperpolarizing afterpotential is similarly prolonged by cooling (86,136). These findings are consistent with the differential effects on ion activity noted above (86). On the other hand, a crossover point of the rise and fall functions occurs at about 20 ° C in the squid giant axon (65). This temperature is probably about the upper limit of environmental temperatures experienced by this animal. The Q~0s of the duration of the sodium-dependent portion of the action potential in mammalian cells increases biphasically as temperature declines over a wide range. This occurs, for example, in sodium currents in an in vitro preparation of myelinated motor nerve fibers of the rat (121). The Q~0 increases from 1.14 between 20 and 40 ° C to 1.85 between 0 and 10 ° C with a transition area between 10 and 20 ° C (121). Similarly, as noted above with regard to acclimation temperatures, a change in sodium channel activation characteristics occurs at temperatures below 10 ° C, and the transition temperature is lower in frogs living in a cooler climate (123). This difference was attributed to a possible structural transformation in sodium channel proteins or the surrounding iipids (123). Romey and colleagues (115) have reviewed this issue, emphasizing the likelihood that within a critical temperature range, around 18 to 8 ° C, the lipid environment of the ion channel is gradually changed from a fluid-like to a solid-like state. Amplitude. The depolarization of the resting cell membrane and the decrease in ion conductances associated with cooling suggest that the amplitude of an action potential will be smaller. Increased resistance may, on the other hand, result in spikes that are larger than normal once the cell has exceeded the firing threshold. In fact, the amplitude of the single cell action potential has been reported to both decrease with co.ling and increase with cooling. Table 2 presents reported temperature coefficients for action potentials recorded from different preparations. In addition to the data of the table, decreased action potential amplitude with cooling (Qt0s greater than 1) has been observed in green frog sciatic nerve (48), in cat spinal mot,neurons (110), and in antidromically stimulated cerebellar Purkinje cells of goldfish (46). Ion current amplitudes associated with excitation have been reported to be reduced consequent to cooling (58,76,84,115,121). The Q~0sof peak sodium currents increase from 1.1 between 40 and 20 ° C (121) to 1.9 or more between 10 and 0 ° C (84,121). Some factor other than ion currents as recorded in vitro therefore must account for the contrasting findings cited in Table 2. Besides the studies cited, increased spike height pro-

TABLE 2 TEMPERATURE COEFFICIENTSOF ACTION POTENTIALAMPLITUDES Q~o 1.3 1.0-1.4

0.83 0.97 0.78-0.62 0.91 0.4 0.87

Temperature 5-20 ° C 4-18 ° C 8-25 ° C 2-20 ° C 20-35° C 6-24* C 21-31 ° C 27-37* C

Preparation

Ref

Spring toad motor nerve fiber Lobster bifurcating mot.neuron Frog medullated peroneal fiber Squid giant axon Squid giant axon Squid giant axon Human nerves of arm and hand CA! neurons, hippocampal slice

(134) (58) (119) (65) (71) (142) (13) (136)

T H E R M A L INFLUENCES ON NEURAL FUNCTION portional to temperature reduction (Qm0sless than 1) has been reported in cat spinal motoneurons (18,86). Calciumdependent characteristics of the hyperpolarizing afterpotential, i.e., its duration and amplitude, also increase in response to cooling in hippocampal CA1 neurons in vitro, following a pulse train (136). It may be that the increased duration of the action potential increases calcium entry and, therefore, calcium ion-activated potassium conductance, despite the slower rate of entry of calcium ions (136). Alternatively, cooling may decrease the rate of calcium buffering and sequestration by energy-dependent mechanisms, which would result in increased calcium inside the cell, and thus in prolonged and larger calcium-activated potassium currents. Results from in vitro studies of ion activity do not enlighten the picture because the amplitudes of calcium currents are reduced at lower temperatures (19,24,87,93,106), as are potassium currents (75,115). The peak unit amplitudes of calcium currents are weakly temperature-sensitive, but the temperature effect on peak calcium current amplitude appears to be more the result of prolonged delays between channel openings at lower temperatures (106). Hodgkin and Katz (65) discussed the conflicting results on amplitude, suggesting that the greater prolongation of the changes underlying the decay phase, with respect to those of the rise of the action potential, may be responsible for increased amplitude due to cooling. In other words, the spike may continue to grow until the delayed decay processes cause it to diminish. This would explain Q~0 values less than 1, but not the contradictory findings. A number of factors can be ruled out because both findings have appeared in conjunction with them: peripheral vs. central nervous system, poikilotherms vs. homeotherms, in vivo vs. in vitro preparations, large vs. small fibers, myelinated vs. unmyelinated fibers, warming vs. cooling, cell body vs. axonal recording. There is some evidence that orthodromic and antidromic stimulation produce different amplitude-temperature functions in the compound action potential, with the antidromic effect being greater than the orthodromic, although both effects are in the same direction (13,63). A U-shaped function is suggested by unquantified tracings of antidromically evoked compound action potentials of the horseshoe crab optic nerve (3). While amplitudes are not discussed in that report, the plotted action potentials appear to first increase then decrease as the nerve is cooled from 27.2 to 8.2 ° C (3). Bipolar and monopolar recordings display similar changes in amplitude in warmed whole nerves (13). One parameter that may account for a portion of the conflicting findings is the time course of the temperature change. An immediate change in input resistance following a change in temperature, and a time lag in the depolarization response, as reported by Pierau, Klee, and Klussman (110) in the cat (described in the section on resting membrane potential) could be responsible for increased spike amplitude during and immediately following a temperature shift, and decreased amplitude after temperature stabilization. Most reports do not specify the time periods involved in the recording procedure, but there seems to be nothing to contradict this hypothesis at this time. Another factor that accounts for amplitude differences is the site of cooling with reference to the recording and stimulating sites. The amplitudes of compound action potentials are affected differentially depending on the portion of nerve trunk that is cooled (18,89). Action potentials of peripheral nerve in awake cats increase in amplitude and duration when reaching a cooled segment of dorsal root (18). Nerves cooled "locally" at the recording site or cooled "segmentally" (i.e.,

403 more broadly between stimulation and recording sites), respond differently to antidromic stimulation. Action potentials recorded from the median nerve of the wrist and hand and the sural nerve of the calf in awake humans increase with local cooling (Qi0 about 0.5 between 30 and 20 ° C) and decrease with segmental cooling (Q~0 about 1.5, 20 to 35 ° C). With local cooling, the Q~0s for amplitude and spike rise time are nearly identical, suggesting that the same mechanism is involved. Under the Hodgkin and Katz hypothesis however, decay rate and amplitude should have the same temperature coefficients, but it is clear that decay is more affected than rise time. The time course and site of cooling may account for some of the apparent contradiction in the amplitude effects seen in different experiments, but it may not explain the differences in single unit studies where cooling is done by bathing the cell. There seems to be no simple resolution to this question, and it may be that some combination of factors, such as cell type and procedures, are responsible. Conduction velocity. The rate at which the action potential propagates is affected in a straightforward way by changes in temperature. Cooling not only slows ion kinetics in the generation of the action potential, it also induces changes in cable properties that slow the spike's propagation down the neuron. This is the mechanism by which conduction velocity is decreased when temperature is reduced, a phenomenon first demonstrated in peripheral nerves by Snyder in 1908 (126). Since that time, the effect has been demonstrated in the peripheral nerves of a number of different animals, as presented in Table 3. In addition to those cited in the table, slowing of the action potential has been reported in the frog (48), cat (108), and lobster (58). Decreased conduction velocity with cooling occurs in vivo in the brain of the rabbit (133). The relationship of conduction velocity to temperature in rabbit and frog nerve fibers has been compared directly (113). The function is much steeper in rabbit (Q~0 about 3.7 between 20 and 40 ° C), than in frog (Qt0 about 1.5, 15 to 36 ° C). It is not clear why the rabbit data should differ so greatly from those for guinea pig (35). Conduction fails above 40 ° C in both rabbit and frog nerve fibers (113). A conduction velocity Q~0 of 1.8 has been observed for a number of vertebrates and invertebrates generally (22). The latency of the propagating action potential reflects conduction velocity, and is increased by cooling (13,48,119, 133,134). Myelinated and unmyelinated nerves respond to temperature change in the same way with respect to conduction veloc-

TABLE 3 TEMPERATURE COEFFICIENTSFOR CONDUCTION VELOCITY OF THE ACTION POTENTIAL IN PERIPHERAL NERVES Q,o

Temperature Range

Species

Ref

1.8 1.7

5-20 ° C 10-20° C 30-40 ° C 20-30 ° C 21-31 o C 20-38 ° C 20-40 ° C 15-36 ° C

Toad Horseshoe crab Guinea pig Guinea pig Human Human Rabbit Frog

(134) (3) (35) (35) (13) (74) (113) (113)

1.3 1.5 1.5 1.5

3.7 1.5

404 ity (62). Qj0s of 1.6 to 4.8 between 37 and 8 ° C in myelinated cat vagus have been found (109). In unmyelinated (desheathed) rabbit vagus nerve QJ0 values increasing from 1.7 to 3.5 between 30 and 0 ° C have been reported (69). Recordings from human fast and slow fibers show no difference between their responses to cold (74). Neurons have limits of cold and heat at which conduction is blocked altogether. Conduction is blocked in cells from poikilothermic and homeothermic animals over the same range of cold temperatures, about 5 to 10 ° C (46,108), although maintenance of conductance and normal amplitude down to - 1o C has been reported in squid giant axon (65). There is no relationship between conduction velocity and the temperature at which conduction block occurs (108). The compound action potential blocks about 6 ° C higher than the single unit spike (108). Heat block occurs above 35 ° C in ceils of poikilotherms (65). Conduction blocks occur more easily in branched axons for which the ratio of pre- and post-branch fiber diameters is above a critical value. This critical ratio is very dependent on temperature (78,142). The ratio is smaller at higher temperatures and larger at lower temperatures. Thus, conduction block in branched axons is more likely at higher temperatures and less likely at lower temperatures. Refractoriness increases as temperature goes down, with a temperature coefficient only slightly larger than that of the spike at higher temperatures, but with widening discrepancy at lower temperatures (48,119). In fibers that discharge continuously or spontaneously the interspike interval is increased by reductions in temperature (3,46,108) or, conversely, decreased by warming (133). MONOSYNAPTIC RESPONSES TO ALTERED TEMPERATURE

Temporal Effects at the Synapse Spontaneous presynaptic neurotransmitter release at the neuromuscular junction is reflected in miniature end-plate currents (MEPCs) and potentials (MEPPs). A number of studies reviewed by Hubbard, Llin~is, and Quastel (70) indicate that the frequency of MEPPs is strongly affected by temperature, with Q~0 values ranging from 2 to 8, and that this effect is probably not the result of cold-induced depolarization at the terminal. The duration of MEPCs increases with decreasing temperature due to prolongation of the decay phase (31,114). The rate constant of the half-decay time in the frog has a Q~0 of about 0.2 between 15 and 6 ° C (31). The end-plate potential (EPP) evoked at the neuromuscular junction, in contrast to the spontaneous MEPP, displays a rising phase that is more sensitive to temperature than its falling phase. Or0s of about 0.4 for the rise and 0.5 to 0.8 for the decay are cited by Hubbard et al. (70). Events evoked at the synapse by a presynaptic action potential, i.e., release of neurotransmitter substance, diffusion across the synaptic gap, and response of the postsynaptic cell, are all sensitive to temperature. The synaptic delay, defined by Katz and Miledi (81) as the latency between pre- and postsynaptic membrane currents, is prolonged by as much as several milliseconds at low temperatures. In frog neuromuscular junction, for example, the minimum synaptic delay exhibits a Q~0 of about 0.3 between 19 and 2 ° C (81). This coefficient agrees well with that reported for the giant synapse of the squid stellate ganglion (90), and with the Q~0 of 0.2 between 20 and 10 ° C reported for Limulus (horseshoe crab) eye inhibitory synapse (3).

JANSSEN The factor most responsible for the increased synaptic delay is the period required for release of chemical transmitter, rather than the time taken for diffusion or postsynaptic reaction (81). This is the result of the release of neurotransmitter substance being more dispersed in time at lower temperatures (81). There is close similarity between the large temperature coefficients describing the kinetics of transmitter release and those of the decay phase of the action potential lengthened by cooling (81). It has been suggested that the calcium ion entry triggered by an action potential and governing neurotransmitter release may be a link between these responses to temperature change (81). High-threshold calcium channels have been implicated in neurotransmitter release (137). As mentioned in the section on action potentials above, these high-threshold channels are distinguished by their high Qj0s of 5 and 3.5 for activation and inactivation, respectively (106). These values compare well with the iQjos for synaptic delay, which range from about 3 to 5. The large temperature dependence of the synaptic delay with respect to that of conduction velocity (Qj0s from most studies were between 1.3 and 1.7) suggests that delay at the synapse may be a greater contributor to increased latencies of evoked potentials than conduction velocity. Further indirect evidence of the greater importance of trans-synaptic excitation is its blockage with less cooling than for conduction block. In anesthetized cat saphenous nerve and brainstem, synaptic block occurs at 15 ° C and conduction block at 0 to - 10 ° C (10). Stevenson, Collins, Randt, and Saurwein (129) provide data for conduction times for both nonsynaptic and monosynaptic somatosensory evoked potentials at 37 and 27 ° C. Inverted Q~0s(iQ~0s) calculated from their data are about 1.6 for the nonsynaptic and about 2.0 for the monosynaptic latencies. The relative importance of delays of conduction and synaptic excitation has been directly studied in the somatosensory pathway of the anesthetized rat (21). Recording from fibers pre- and postsynaptic to the cuneate nucleus, cooling by 10 ° C increased conduction time in the spinal dorsal column by 26O7o (iQjo = 1.25), whereas the synaptic crossing increased by 106o7o (iQio = 2). In the Limulus (horseshoe crab) eye neural network, using light to stimulate excitatory and lateral inhibitory processes, Q~0s of less than 2 characterize nonsynaptic processes including conduction velocity, and the synaptic delay has a Q~oof 5 (3).

Postsynaptic Excitability Evidence on the postsynaptic excitability of cooled and warmed neurons is equivocal. Pre- and postsynaptically recorded potentials from an in vitro preparation of squid giant synapse have been compared (139). At 18 to 20 ° C the excitatory postsynaptic potential (EPSP) almost always generates an action potential, but this becomes less likely as temperature is reduced. This result is attributed to the size of the EPSP, which is diminished by cooling, rather than to an increased threshold. At low temperatures, i.e. about 9 ° C, there is a failure of the EPSP to initiate a spike (139). A similar result occurs in goldfish Purkinje cells (46). In conflict with these studies are data on the EPSP and the likelihood of a spike occurrence in cat spinal motoneurons, using a double shock to evoke an EPSP (I10). Cooling by 1 to 2 ° C renders the second EPSP more likely to trigger a spike and, with further cooling, the first EPSP consistently produces an action potential. The increased excitability may be attributable to larger EPSPs resulting from rapid cooling

THERMAL INFLUENCES ON NEURAL FUNCTION (110). Alternatively, given an increased time constant in conjunction with increased resistance, the EPSPs may simply undergo more temporal summation. From these studies it is not possible to determine whether postsynaptic excitability is altered by temperature change because it is not separable from EPSP amplitude. As in the case of the contradictory data on intraneuronal excitability, it is possible that differences in the preparations and absolute temperatures used may account for the findings. Also, for poikilotherms, the prior acclimation temperature of the animal has a substantial effect on many neurophysiological responses to temperature change (11 l) including the synaptic blocking temperature (46). Monosynaptic inhibition is less effective in cooled neurons (46). This effect has been observed in the goldfish cerebellum, in the inhibition of ongoing Purkinje cell activity following stimulation of climbing fibers. The duration of inhibition following an inhibitory postsynaptic potential (IPSP) decreases in these cells as temperature is reduced by local cerebellar cooling, followed by reduction and disappearance of the IPSP (46).

Postsynaptic Response Amplitude With cooling, the amplitudes of postsynaptic responses may either increase or decrease, depending on a number of factors. In monosynaptic single unit responses in the cerebellum of curarized goldfish, both EPSPs and IPSPs of individual Purkinje ceils decrease monotonically from 25 ° to as low as 6 ° C (46). Data from mammalian hippocampal slices are consistent with these findings in that GABA-mediated, chloride-dependent IPSPs of single units decline as temperature falls from 37 to 33 ° C (136). Neurons of the dorsal root ganglia of the bullfrog, Rana catesbiana, exhibit peak GABAgated chloride currents which are maximal at 25 ° C and diminish both above (Q~0 approximately equal to 0.5) and below 25 ° C [Q~0 about 1.1, based on data presented (42)1. These findings accord with others from neurons of Aplysia, in which conductances of GABA-gated chloride ion channels are slightly diminished by cooling from 22 to 12 ° C (85). In the same Aplysia neurons, however, responses of chloride channels to glutamate are greater at 12 ° than at 22 ° C, with a Q~0 of approximately 0.7 (85). But responses of ion channels coupled to agonists of the glutamate receptor subtype, NMDA, diminish when temperature is reduced in cultured rat hippocampal neurons. The amplitudes and mean open times of the NMDA-linked channel are strongly affected by temperature with Q~0 values for current amplitudes and iQ~os for mean open time greater than 2.8 in response to NMDA and two of its agonists (100,101). The similarity of the temperature-dependencies of amplitude and channel open time may indicate that both are affected by the same process, such as changes in the conformation of the channel (100,101). The findings on glutamate-gated channels are not contradictory because NMDA-induced current includes both sodium and calcium ion currents. The EPSPs of single motoneurons of the anesthetized cat increase with slight cooling, although repetitive stimulation of the dorsal roots or sensory nerves results in reduced amplitudes of subsequent EPSPs (110). This enhancement of the response to single stimuli occurs in rapidly cooled tissue despite slight reductions in the presynaptic action potential, and is attributed by the authors to the time course of increased membrane resistance cited in the section on membrane properties, above.

405 Postsynaptic population potentials (PSPPs) in response to single fiber stimulation in a cat spinal in vivo preparation show a rather linear increase as the temperature is reduced from 41 to 35 ° C (92). The correlation between temperature and amplitude, about - 0.9, is statistically significant. At each selected temperature in the range used, a combination of cooling and post-tetanic potentiation yields larger population responses than cooling alone. Increased amplitude with cooling may be attributed to better conduction at axon branch points, the result of longer action potential duration (92). Measuring postsynaptic potentials at squid giant synapse, conflicting results have been reported. Consistent with findings in the cat in vivo, Lester (90) observed larger amplitudes due to cooling. But a similar preparation studied by Weight and Erulkar (139) exhibited smaller PSPs at lower temperatures. A curvilinear decrement of I0 millivolts to about 1.5 millivolts was observed between 10 and 6 ° C. The postsynaptic amplitude did not precisely reflect presynaptic action potential amplitude, although the direction of effect was the same. The authors concluded that factors other than spike amplitude influence the amplitude of the postsynaptic response 039). This is consistent with the conclusion of Katz and Miledi (81) that it is the greater duration of action potential decay that is responsible for a greater amount of transmitter release. These opposing results observed in what is virtually the same preparation underscore the paradox presented by data on spike amplitude in a preceding section. Again, it may be subtleties of procedure which account for the conflict. The difference in the amplitude findings of Lester (90) and Weight and Erulkar 039) in squid giant synapse may be explained if the time course of cooling differed in these experiments. In general, increased resistance may have been the dominant factor in experiments yielding high amplitudes, and depolarization the dominant factor in the diminution of amplitude with cooling. Results of experiments conducted at the neuromuscular junction provide a rather consistent picture. Spontaneous transmitter release, as reflected in MEPPs and MEPCs, is reduced at cooler temperatures (31,114). Q~0s for MEPC amplitude of 2.4 between 15 and II °, and 3.0 between II and 6 ° C have been reported (31). It is suggested that the decline in amplitude with cooling could be the result of reduced postsynaptic affinity of the receptor, changes in the receptor channel opening rate constant, or a reduction in the number of receptor channels available at low temperature (31). Evoked responses to neurotransmitter release at the neuromuscular junction, EPPs and EPCs are generally increased by cooling. Hubbard, et al. (70) cite reports which show that acetylcholine, the transmitter present at most of the synapses studied, displays increased effectiveness at cooler temperatures, and that the output of cholinesterases is reduced (QJ0 = 1.3-1.5). EPP amplitudes are markedly altered at temperatures that have little effect on MEPPs (70). Postsynaptic depolarizations in response to acetylcholine at the junction of rat phrenic nerve and diaphragm are likewise larger at 20 ° than at 37 ° C (59). Contractile responses of vascular smooth muscle to norepinephrine in the dog are also augmented at 20, 15, 10 and 5 ° C, followed by a slow decline to control values at 5 ° C (117). The response at the neuromuscular junction to single and repetitive stimuli is consistent with the differential effects on spinal motoneurons discussed above. Findings reviewed by Hubbard, et al. (70) show that temperature-induced variation in the amount of acetylcholine released at neuromuscular

406 junctions by single stimuli is small compared with the marked reduction during repetitive stimulation. The difference is attributable to transmitter depletion and slow synthesis (70). It appears that, at least in poikilotherms, postsynaptic responses are greatest at the acclimation temperature of the animal being used. Prosser and Nelson (111) have reviewed this phenomenon, finding inverted U-shaped functions for a range of measures of postsynaptic response. The principle may also apply to homeotherms, which seem to display reduced response levels above their normal temperatures, as described in previous sections. For poikilotherms, the range of acclimation temperatures is great and may account for much of the apparent contradiction in amplitude data across experiments. Excitatory and inhibitory neurons may respond differently to cooling. Field potentials attributed to the activation of the excitatory granule cells by mossy fiber stimulation are enhanced by cooling from 14 to 10 ° C. Inhibition in this preparation is more temperature-sensitive and is capable of modulation by temperature acclimation of the animal (46). In addition to acclimation temperature and excitatory or inhibitory action, other candidates for reconciling contradictory amplitude data in the nonsynaptic or monosynaptic preparation include site of cooling, time course of cooling, and the cellular recording site. MULTISYNAPTIC RESPONSES TO ALTERED TEMPERATURE: EVOKED POTENTIALS There have been many investigations of the effects of temperature, especially hypothermia, on the peak latencies and amplitudes of multisynaptic evoked potentials [e.g., (21,25, 29,38,49,77,83,94,95,96,98,116,120,127,130,135,144)]. Most of these either have employed anesthesia to experimentally induce hypothermia, a well-known effect, or have involved the recording of evoked potentials during surgery under general anesthetic (95,116,129,144). Clinically, sensory evoked potentials are useful for monitoring the functional state of patients, especially during life-threatening procedures such as cardiac surgery [see, for example, (95)]. A number of anesthetic agents have been shown to increase the latencies of peaks in evoked potentials over and above the effect of hypothermia, and peak amplitudes are affected in more complicated ways (32,60,73). Emphasis will therefore be placed on the few findings which are not confounded by drug effects, with reference to others which are particularly informative about specific issues. Peak Latencies Hypothermia increases the latencies of peaks in the waveforms recorded from sensory systems, and hyperthermia decreases them (9,17,44,60,73,82,97,104,129,131 ). The nonsynaptic Q~0 agrees well with peak latency Q~0s of 1.5 to 1.6 reported by Williston and Jewett (144) for the multiple peaks of the brainstem auditory evoked response (BAER) of anesthetized rats. Williston and Jewett pointed out the close agreement of these values with axonal conduction velocity Q~0s [about 1.6; (144)]. It is surprising that the multisynaptic temperature coefficients for the BAER are not greater, given the even higher values for synaptic delay, and the number of synapses involved (about 4). But a conflicting report (129) indicates that conduction velocity in the somatosensory system is more affected than synaptic delay between 33 and 25 ° C, in unanesthetized cats immobilized with gallamine triethiodide. A number of factors are involved at this level of response, including desynchronization of impulses in the pathway, which

JANSSEN may mask the temporal relationships seen at finer levels of analysis. BAER peak latencies correlate negatively with oral temperature within the approximately 2-degree range of diurnal variation in humans (9,17,97). Latencies of cortical evoked auditory responses are not significantly delayed down to an oral temperature 4 ° C below normal in a study of humans immersed in cold water, although a few subjects appear to display an effect (44). Over a larger temperature range, BAER peak latencies in unanesthetized sheep (1 04) and alligator (131) are also negatively correlated with temperature. Peak Amplitudes The literature contains scores of reports on the temperature sensitivity of mammalian sensory evoked potentials recorded from anesthetized and otherwise drugged subjects. The studies report both decreased and increased amplitudes in hypothermia, as well as variable and curvilinear relationships. Anesthetic effects are complex. In a study of a number of different anesthetic agents, evoked potential amplitudes vary too widely within animals and sessions, and across different compounds, to be useful (32). BAERs recorded from both awake and pentobarbital-treated rats at temperatures ranging from 37.5 to 31.5 o C show complex drug and temperature interactions (73). In untreated rats, cooling monotonically increases the amplitudes of all peaks in the waveform, by as much as 25°70 in the final and most affected peak. Pentobarbital anesthesia prevents this increase in the later peaks, but augments the earlier peaks (73). Visual evoked potentials of rats display a different pattern, however. In a series of experiments, treatment with chloral hydrate or with a mixture of chloral hydrate and pentobarbital (Chloropent) in conjunction with cooling produces waveform augmentation. But hypothermia alone produces both no significant change in amplitude of pattern reversal visual responses, or reduced amplitude of responses evoked by light flashes (36,60,61). Studies of hyperthermic humans (99) and hyperthermic sheep (104) and alligators (131) report amplitude decrements in the absence of drug administration. Raising oral temperatures of normal human subjects by about 1° C reduces the amplitude of visual and somatosensory evoked potentials (99). BAER amplitudes are diminished when brain temperatures of sheep are raised by about 5 ° C (104). These findings are consistent with a negative correlation between temperature and amplitude, but such a correlation is not found in the visual evoked potentials of rats, where amplitudes are unaffected or reduced by cooling, as cited above. In unanesthetized alligators, there is a positive correlation between temperature and BAER amplitude over the temperature range of 0 to 36 ° C (131). Several factors hypothetically may contribute to these discrepancies: (a) relative stability of temperature over time; (b) sites of cooling, stimulation, and recording; (c) stimulus characteristics; and (d) fundamental differences in the sensitivities to temperature of portions of the nervous system. Both increments and decrements in amplitude occur within different portions of the somatosensory system in awake cats. Somatosensory evoked potentials from the dorsal column of the spinal cord, from the thalamus, and from the reticular formation of awake cats immobilized with gallamine triethiodide have been recorded (129). Spinal cord potentials increase at temperatures between 33 and 25 ° C, but decrements are noted in the midbrain structures. These temperatures were rectally measured, and it is possible that there was a temperature differential along the axis. In addition, stimulation took place peripherally, while cooling was accomplished by placing

T H E R M A L INFLUENCES ON NEURAL FUNCTION the animal in a pan of crushed ice. Some temperaturedifferential effect akin to the "local" vs. "segmental" cooling phenomenon (89) may have been operating. As presented in the section on action potential amplitudes, above, local co,ling at the recording site yields increased amplitudes, while broad cooling of the nerve segment between stimulation and recording sites results in amplitude decrements. There also may have been a difference in the rapidity of cooling of the different structures in the cat somatosensory system experiments (129). This factor, as discussed previously, affects the direction of amplitude changes. Site of cooling is not a significant determinant of amplitudes of evoked potentials of the cuneate nucleus, however (4). Evoked field potentials increase with cooling in anesthetized cats with all of several cooling techniques: local perfusion of cortex of cuneate nuclei, cooling of the cuneate surface by means of a cooling chamber, systemic cooling by immersion in ice, and extracorporeal cooling of recirculated blood (4). Anesthesia presents a confound in these findings and in those of Lang and Puusa (89) on local and segmental cooling. In the data from unanesthetized subjects, there is not a consistent effect of temperature on evoked potential amplitudes. There may be inherent differences in the sensitivities of different neuronal types, as suggested by some [e.g., (38)], or the combined effects of rapidity and site of cooling may be operating to produce the inconsistencies. In the study of rat BAERs cited above (73), cooling was accomplished by placing animals in a cold room at 4 ° C until colonic temperature reached a target level (a matter of minutes), and colonic temperature was changing during the measurement period (73). In the series on visual system evoked potentials (36,60,61), rats were cooled for 2 hours in a room at 17.9" C, perhaps providing a more stable and uniform hypothermia. Temperature may also have been changing during the measurement periods of some experiments on hyperthermia (99,104). It has been reported that, in recording from anesthetized rats, amplitudes are large when temperature is unstable, but they return to normothermic levels as temperature stabilizes (144). Similarly, fast cooling augments evoked field potentials of the cuneate nucleus more than does slow cooling in anaesthetized cats (44). When the temperature of a cooling bath is stabilized for 15 to 30 minutes, decreased amplitudes of alligator BAERs are observed at lower temperatures (131). Much of the discrepancy with respect to amplitudes may thus be attributable to the differential time courses of membrane resistance and membrane potential during and following cooling, cited previously (110). Depolarization of the membrane in its resting state may reduce the size of a subsequent action potential, while increased membrane resistance may result in greater spike amplitudes. Therefore, if temperature is shifting during measurement, these changing membrane properties may alter the size of the action potential, with the direction of the change depending on the time course of the cooling. Another factor that may affect data collected from awake animals is whether shivering is prevented through immobilization by gallamine triethiodide. Impedance changes are statedependent in focal areas of dorsal hippocampus, amygdala, and rostral midbrain reticular formation of awake cats (2). Resistive and capacitive impedance are affected by sensory stimulation, by the level of carbon dioxide in brain compartments, and by the animal's mobility. In shivering animals, both reactive and resistive impedance are relatively stable until core temperature falls to about 25* C. Between 25 and 21" C, both reactance and resistance rise sharply. In contrast, immo-

407 bilized cats show immediate increases of resistance and capacitance as temperature drops from 38 to 30 ° C, and this trend continues to the lowest temperatures. During rewarming, recovery of impedance in both the shivering and immobilized preparations lags behind temperature recovery (2). A similar hysteresis has been reported in the cuneate nuclei of anesthetized cats (4), but is not seen in the cerebellum of anesthetized cats (38). Differential temperature sensitivities of nuclei and/or cell types of the nervous system may exist. Impedance characteristics of the rostral midbrain reticular area are less affected by hypothermia than are the hippocampus and amygdala (2). This is consistent with other findings in anesthetized cats (98). But the amplitudes of evoked potentials of the afferent midbrain reticular formation are more sensitive to hypothermia than are the spinal cord and thalamic relay nuclei (129). This agrees with the finding that the reticular activating system is the brain area least resistant to cold in unanesthetized hamsters arousing from hibernation (28). Thus, large regions of the brain may be more or less affected by changes in temperature. Cell types, too, may be differentially sensitive. In the peripheral auditory nervous system of mammals, evoked potentials of the receptor hair ceils and of the postsynaptic auditory neurons are altered differentially by cooling (23,30,41,80, 125), and the amplitudes of hair cell-related potentials do not predict amplitudes of the auditory nerve compound action potential (23,30,80). The differences between cell types are both quantitative and qualitative. For example, the receptor hair cells, unlike auditory nerve cells, may display threshold elevations and reduced turning, or frequency specificity (125). Moreover, this effect occurs selectively at ceils sensitive to high-frequency sound, i.e., those at the basal end of the organ of Corti, despite the uniformity of temperature throughout the length of the organ of Corti (125). Tuning in the turtle cochlea is dependent on the resonance frequencies of calciumactivated potassium conductances, and the fast inward calcium current may dominate tuning at the higher frequencies (7). High-threshold calcium currents are more temperaturesensitive than are other ion currents (106), and it is interesting to speculate whether a type of calcium current that is especially affected by temperature may account for the differential frequency-related effects of temperature in the mammalian organ of Corti (125). Whatever the mechanism, it appears that the peripheral auditory system of mammals may comprise cell types that respond differently to cooling, other things being equal. Others have reported differential sensitivities of neuronal cell types. For example, cooling differentiates mossy fiber from climbing fiber inputs in the anesthetized cat, and other differential responses to cold are found in different layers of the cerebellum (38). Chang (26), however, has emphasized that anesthesia affects dendritic and axonal components differently. Neurons have different intrinsic firing patterns related to the functions they perform in the nervous system. The factors that may underlie these firing patterns, such as the characteristics of the particular collection of ion channel types present, may form a basis for differential responses to cooling and warming by different cell types. The many different and interacting types of postsynaptic receptors and modulating influences may possibly be involved in determining evoked potential response amplitude. Changing membrane properties may also underlie the contradictory findings with respect to EPSP size and firing threshold discussed in previous sections. This in turn may be re-

408

JANSSEN

flected in the numbers of neurons contributing to the amplitudes of evoked potentials, whether their peaks comprise action potentials or EPSPs. It has been pointed out that the prolongation of individual action potentials would result in greater temporal overlap and, thus, increased amplitudes of field-recorded action potentials (113,132). Conversely, others note that desynchrony of firing could bring about smaller peak amplitudes of compound action potentials (88). The decreased likelihood of branch point failure at reduced temperatures would be expected to result in larger amplitudes, due to facilitation within the axon terminal field. Stimulus characteristics are important in determining the amplitude of the auditory nerve action potential in response to cooling. Two manipulations systematically affect the amplitude of the auditory nerve action potential: acoustic stimulus frequency and stimulus level. The AP is reduced by cooling when stimuli are presented at low levels (40 to 70 dB sound pressure level) and augmented by cooling at high stimulus levels [70 to 120 dB sound pressure level; (23)]. Secondly, auditory nerve responses to high acoustic frequencies are more affected than low-frequency responses (20,125). Perhaps differences in stimulus level and spectrum, as well as in species sensitivities, may contribute to the poor agreement among auditory EP studies. Stimulus characteristics such as intensity may similarly affect responses of other neural systems. DISCUSSION In large measure, thermal influences on neural function can be predicted using existing formulations. Where the predictions diverge from measurements, many of the parameters requiring adjustment are now known. Resting membrane potential as predicted by the Nernst equation is linear with temperature. However, membrane potential is better predicted by consideration of differential ion permeabilities, as in the Goldman-Hodgkin-Katz equation. It is now known that these permeabilities are themselves affected by temperature. Other factors that affect the relationships include the resting potential at the onset of cooling, an animal's acclimated temperature at sacrifice, the interaction between the operation of membrane ion pumps and the time course of temperature change, the location within the neuron where measurement takes place, and the time course of temperature change. Unknown influences may be exerted by ion conductances of types that have come to light since the original formulations. Q,0, the conventional expression of the rate of change in measured values across a temperature range, reflects all of these factors. The relationship between Q~0 and rates of biochemical reactions as predicted by the Arrhenius equation is, therefore, not very clean. The multiplicity of factors affecting neural function at different temperatures necessitates the specification of precise measurement and tissue conditions whenever Q~0 values are reported. The temperature dependencies of action potential parameters are predicted well by the Hodgkin-Huxley formulations, expressing cable and conductance properties. The highest Q~0s among these are about 1.2 to 1.4. There are discrepant reports of effects of cooling on spike threshold, however, and this phenomenon may have multiple determinants, such as the measurement location within the neuron. The differential time courses of membrane resistance and depolarization may also play a part in determining cable and conductance properties. Temporal characteristics of the action potential seem to be straightforward: Cooling slows both ion activation (Q]0s of 1.7 to 3.1) and the conduction of the spike (Q20s mostly be-

tween 1.3 and 1.8), and increases the spike's duration (iQ~0s of 1.7 to 3.3). Calcium-activated potassium ion efflux is increased in consequence of increased duration, both of which may be secondary to temperature-dependent pump activity. The hyperpolarizing afterpotentiai is also increased in duration, perhaps the result of prolonged calcium ion entry. The effect of cooling on synaptic delay is more dramatic. Inverted Qi0s (iQ,0s) of 3 to 5 are reported for synaptic delay, with the dominant component being transmitter release. This may be associated with the prolonged decay of the action potential and resulting increase in calcium ion entry. The temporal effects of cooling are straightforwardly reflected in increased latencies of peaks of evoked potentials in hypothermic animals, and correspondingly decreased latencies in hyperthermia. The relationship of amplitude to temperature is more complex than latency at each stage of analysis, from single unit activity to postsynaptic potentials to multisynaptic evoked potentials recorded in the far field. In some studies, amplitudes decrease as a result of cooling, and in others they increase, are curvilinear, or do not change. This is true even within the sets of experiments using similar preparations. It is likely that much of the inconsistency may be accounted for by the extent of temperature change over time, and the distribution of temperature change throughout neural tissue. Membrane characteristics are differentially affected by the time course of temperature change, making the direction of change in amplitude dependent on which underlying membrane changes are occurring at the time of measurement. Whether the probability of firing is decreased or increased in a given experiment may also be determined by the rate of change of temperature. In sum, it appears that cooling induces a cascade of progressively increasing changes beginning with resting membrane characteristics of relatively low temperature sensitivity. Properties related to the action potential are somewhat more sensitive to temperature, particularly in the decay phase. The final intracellular events, especially the release of transmitter substance, are highly temperature-dependent. APPENDIX GENERAL EFFECTS OF TEMPERATUREON NERVOUS SYSTEM FUNCTION Metabolic Processes Because biochemical processes slow when cooled, fewer metabolic resources are used at lower temperatures. This is why, in surgical procedures requiring reduction of cerebral blood flow, induced hypothermia can have a protective effect on brain tissue (43,91). For example, at normothermic temperatures the duration of circulatory arrest necessary to produce permanent neurological damage in animals is 4 to 6 minutes. Hypothermia has been found to increase this critical duration to 20 to 29 minutes. The protection offered has been attributed to the reduced metabolic energy required by synaptic transmission, operation of ion pumps, and other neural processes (43). Hypothermia may affect the absolute amounts of certain metabolites in whole brain (34). In much of the research on brain metabolism under hypothermic conditions, however, hypothermia is a byproduct of a pharmacologic or toxicologic process, usually either anesthesia or the result of exposure to triethyltin (TET), a potent neurotoxicant. The measures of

THERMAL INFLUENCES ON NEURAL FUNCTION brain metabolism used in these studies, therefore, may have been affected by the chemicals inducing hypothermia or by an interactive chemical and temperature effect, rather than by hypothermia alone. Nevertheless, effects of cooling that seem to be consistent across drugs include reduced amounts of glutamic acid, and considerably increased glucose levels in whole brain. Pyruvate decreases when glucose levels increase. In deep anesthesia, but not after TET sulfate poisoning, lactic acid is significantly lower than normal. Amounts of adenosinetriphosphate (ATP) and phosphocreatine, considered high energy intermediates in cell metabolism, do not appear to be affected in hypothermia (34). Metabolic processes have been studied dynamically by use of radioactive precursors (34). Three endpoints have been explored: incorporation of 32p into phospholipids, amino acids into protein, and ~4C glucose into amino acids. With one exception, these experiments have involved the use of neuroactive drugs. In general, the results are indicative of reduced brain metabolism due to cooling. When severe hypothermia (18-22 ° C) is induced in rats by means of low environmental temperature alone, the amount of 3Zp incorporated into phospholipids is only about 16% of control (138). Other dynamic studies of the production and utilization of high energy phosphate support the conclusion that glucose metabolism is reduced in the brains of animals made hypothermic by chemical exposure (34). Some of the biochemical changes occurring in hypothermia induced by anesthesia can be wholly or partially prevented or reversed by appropriately manipulating the environmental temperature in order to make the animal normothermic. For each compound, it seems a critical environmental temperature may be found at which hypothermia is prevented. Under these conditions and depending on the drug, some of the effects listed above may not occur or may occur at a reduced level. It is important to distinguish among effects, however. In the case of TET, normothermia completely prevents the reduced incorporation of 32p into phospholipids but has no effect on the lethal dosage or the characteristic central nervous system edema produced by this toxic metal. Therefore, neurotoxic processes sometimes may be independent of metabolic processes. Hyperthermia appears to produce neurochemical effects which are the mirror image of those produced by hypothermia, although data are limited in this regard (34).

Blood-Brain Barrier The blood-brain barrier is a multifaceted system that characterizes the interaction between the central nervous system and its vasculature. It has a number of anatomical components, such as tight cellular junctions and small or absent pores and extracellular spaces (140). There are also biochemical and physiological components that are vulnerable to fluctuations of metabolic conditions, potential differences, pH gradients and other physiological factors (112). The bloodbrain barrier appears to have a highly temperature-dependent active transport system effective in the uptake of some sugars [Q~o = 3.0 between 20 and 40 ° C in anesthetized cat; (40)]. The brains of hypothermic mammals absorb more labelled carbohydrates and ions, but not more protein, than those of normothermic controls, although hibernating animals appear to be protected against increased absorption. Poikilotherms also seem to resist uptake of these substances in the brain, whether warm or cold. Neonatal rats, with immature thermoregulatory systems, also exhibit resistance to tracer absorption when hypothermic. Increased deposition of rubidium, an ion

409 tracer, is independent of the duration of hypothermia, and there appears to be a critical brain temperature of 18.8 ° C at which the barrier system breaks down with respect to this substance (140,141). Pharmacologic manipulations may influence the effectiveness of the rubidium barrier during hypothermia. For example, high doses of the synthetic glucocorticoid dexamethasone tend to reduce hypothermic tracer uptake. Ouabain, a drug which disables the sodium pump, permits greater absorption of tracer in the brains of normothermic rats. Although this occurs only at high dosages, it is consistent with the hypothesis that disruption of the metabolic ion pump is involved in the hypothermic disruption of the barrier system (140,141). Hypothermia in these experiments was induced by means of immersion in an ice bath following ether anesthesia (140,141), except in the case of neonatal rats. Ether slows brain metabolism, and biochemical indicators of this effect are increased by cooling (34). It cannot be determined from these studies whether the use of ether played a role in the differential effects of hypothermia. The relative lack of resistance to barrier breakdown seen in adult animals may be in part the result of ether absorption. Likewise, dexamethasone may interact with ether to influence, in either direction, the effects of that drug.

Susceptibility to Insult Cooling slows nervous system metabolism, thus protecting the brain against anoxia. On the negative side, it tends to disable the blood-brain barrier system, allowing the entry of ions, carbohydrates, and possibly other substances as well. Hypothermia accentuates certain effects of some neuroactive chemicals, including pentobarbital, thiopentone, phenobarbital, ether, amytal, chlorpromazine, reserpine, and TET sulfate on brain metabolism (34). This may be due to its effects on the barrier system, but hypothermia does not always increase susceptibility to chemical effects. Hypothermia accelerates recovery from the increased latencies of evoked potentials resulting from TET administration; normothermic animals recover more slowly (37). Similarly, preventing hypothermia induced by carbon monoxide causes death at a normally nonlethal concentration of carbon monoxide (5). This is consistent with the protective effect of hypothermia against hypoxia resulting from interruption of blood supply. The neurotoxic solvent sulfolane behaves similarly in that hypothermia is protective (51). It is clear that temperature plays a very complex role in altering the susceptibility of the nervous system to toxic substances, within a moderate range of temperature variation. In extreme hypothermia, a critical brain temperature is reached at which the blood-brain barrier system breaks down.

Axonal Transport Two types of metabolic transport systems for the delivery of cell components and neurotransmitter substances up and down the axon are often measured. Slow axonal transport occurs at a rate of several millimeters per day and is not sensitive to temperature (56). Fast transport, measured in millimeters per hour, is temperature sensitive in an exponential way, with Qt0s ranging from greater than 2 to greater than 3, depending on the temperature range (12,33,39,56,57). The findings are remarkably similar across preparations and there are no significant differences between rates of transport in in vivo and in vitro preparations of mammalian neurons (12). There is also no difference in transport-temperature relationships between hibernating and nonhibernating animals of the same

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species, indicating t h a t h i b e r n a t i o n provides no e x e m p t i o n f r o m the effect o f cold o n fast t r a n s p o r t rates (12). T r a n s p o r t values observed across t e m p e r a t u r e s in garfish have been ext r a p o l a t e d to n o r m a l m a m m a l i a n t e m p e r a t u r e s (57). T h e ext r a p o l a t e d t r a n s p o r t rates are well within the range observed in h o m e o t h e r m s at n o r m a l body t e m p e r a t u r e , suggesting t h a t t r a n s p o r t m e c h a n i s m s m a y be very similar in phylogenetically widely separated species (57). There is a difference, however, in the t e m p e r a t u r e tolerances o f t r a n s p o r t rate between h o m e o t h e r m s a n d poikilotherms. Both cold a n d heat block axonal t r a n s p o r t . In poikilotherms, cold block occurs at a b o u t 5 ° C (39,57), a l t h o u g h frogs kept at 4 ° C acclimate, showing higher t r a n s p o r t rates below 15 ° C t h a n n o n a c c l i m a t e d frogs (39). T r a n s p o r t in

m a m m a l i a n cells either blocks or undergoes a transition at 13 ° C, a n d is blocked by heat at 47 ° C (12,33). Rapid t r a n s p o r t is sensitive to small changes in t e m p e r a ture. Otherwise intact rats m a d e h y p o t h e r m i c by approximately 2 ° C by the systemic a d m i n i s t r a t i o n o f the f o r m a m i d ine pesticide c h l o r d i m e f o r m exhibit significantly slowed t r a n s p o r t as a result o f the h y p o t h e r m i a r a t h e r t h a n the chemical (14). ACKNOWLEDGEMENTS The author wishes to thank Dr. Robert S. Dyer, Dr. Ben M. Clopton, Dr. William K. Boyes, and Dr. Timothy J. Shafer for careful editorial assistance and helpful discussion. None should be held accountable for the views expressed here.

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