Differential Effects of Escapable and Inescapable ... - Semantic Scholar

Behavioral Neuroscience 1991, Vol. 105, No. 1,202-209

Copyright 1991 by the American Psvchological Association, Inc. 0735-7044/91/53.00

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Differential Effects of Escapable and Inescapable Footshock on Hippocampal Theta Activity Bernard W. Balleine and Ian S. Curthoys University of Sydney, Sydney, New South Wales, Australia Three groups of rats were exposed to escapable shock, inescapable shock, or no shock using procedures known to induce learned helplessness effects. Twenty-four hours later, hippocampal electroencephalograms were recorded from freely moving subjects. A 5-s probe shock was delivered after 15 min, and recording continued. Frequency analyses revealed no differences between the pretreatment groups during the first recording segment. Immediately after the probe shock, however, trains of immobility-related theta activity were observed in both the escapableand no-shock groups. No such activity was observed in the inescapable-shock group. Because immobility followed the probe shock in all groups, this relative impairment was not due to differential motor activity. These results offer in vivo support for in vitro findings suggesting that hippocampal activity is sensitive to event contingencies and is involved in stress-induced learning deficits.

1988; Maier, Jackson, & Tomie, 1987; Minor, Jackson, &

It has been consistently demonstrated that exposure to uncontrollable and inescapable stressors has profound behavioral and physiological effects. For example, after inescapable footshock, rats perform poorly in aversively and appetitively motivated tasks (Jackson, Alexander, & Maier, 1980;Maier,Albin,&Testa, 1973;Rossellini, 1978), become inactive in the presence of shock (Drugan & Maier, 1982, 1983), show reduced aggression and social dominance in a variety of situations (Payne, Anderson, & Murcurio, 1970; Williams, 1982), and exhibit enhanced signs of stress including a general depletion in brain catecholamines (Anisman, Remington, & Sklar, 1979; Weiss et al., 1981), increased analgesic responsiveness (Jackson, Maier, & Coon, 1979), enhanced growth of implanted tumors (Sklar & Anisman, 1979; Visintainer, Volpicelli, & Seligman, 1982), increased gastric ulceration (Weiss, 1968), weight loss (Weiss, 1971), and immunosuppression (Laudenslager, Ryan, Drugan, Hyson, & Maier, 1983). These effects of uncontrollability do not occur when animals are exposed to the same amount and pattern of controllable shock and have been referred to as learned helplessness effects (Maier & Seligman, 1976). In addition to these effects, animals exposed to inescapable shock also show associative learning deficits (Lee & Maier,

Maier, 1984; Rosellini, DeCola, & Shapiro, 1982) thought to be indicative of a more fundamental cognitive deficit (cf. Maier & Seligman, 1976). Although most of the research in this area has examined the psychological mechanisms responsible for these learning deficits, recent evidence suggests that event contingency may directly modulate neural processes at a cellular level (Balleine, McGregor, & Atrens, 1989; Drugan, Mclntyre, Alpern, & Maier, 1985). Of particular relevance in this regard is a recent rinding that inescapableshock, but not escapable shock, impairs long-term potentiation (LTP), a long-lasting enhancement of synaptic efficacy, as measured in vitro in the hippocampal slice preparation (Shors, Seib, Levine, & Thompson, 1989). Because there is evidence suggesting that LTP is involved in learning processes (Berger, 1984; Laroche, Doyere, & Bloch, 1989; Morris, Anderson, Lynch, & Baudry, 1986), an implication of this finding is that inescapable shock induces a learning deficit in vivo through its effects on the mechanisms that subserve LTP. This hypothesis is consistent with previous proposals that the neural mechanisms that underlie learning, or some essential subset of them, are localized in the hippocampus (O'Keefe & Nadel, 1978). Historically, these postulates were initiated and supported using electroencephalographic (EEG) records, particularly those records that attempted to correlate behavioral changes with incidence of rhythmic slow-wave activity (theta activity) in the hippocampus. The appearance of theta activity has, for example, been reported to accompany the performance of voluntary movement (Vanderwolf, 1969), preparatory responses (Grastyan, Karmos, Vereczkey, & Kellenyi, 1966), and orienting responses (Elazar & Adey, 1967; Grastyan, Lissak, Madarasz, & Donhoffer, 1959). In addition, correlations have been reported between theta activity and the rate of acquisition during associative learning

The development of the electroencephalographic recording system was supported by the National Health and Medical Research Council of Australia. We thank Tony Dickinson, Mark Bouton, Chris Montoya, and Debra Trutwein for their helpful comments on the manuscript of this article and Dale Atrens for his technical assistance. Correspondence concerning this article should be addressed to Bernard W. Balleine, who is now at the Department of Experimental Psychology, Downing Street, Cambridge CB2 3EB, United Kingdom. 202

BRIEF COMMUNICATIONS (Berry & Thompson, 1978) and retention of a spatial memory task(Winson, 1978). Interestingly, the evidence derived from both the EEC and LTP paradigms has recently converged in a number of studies that have shown that applying the tetanic stimulus used to elicit LTP at a frequency pattern corresponding with theta activity (i.e., at 5 Hz), clearly enhances LTP compared with patterns of higher or lower frequency stimulation (Larson & Lynch, 1988, 1989; Larson, Wong, & Lynch, 1986; Rose & Dunwiddie, 1986; Staubli & Lynch, 1987). These findings suggest an in vivo mechanism for the generation of LTP because stimulation of the Schaffer-commissural projections in a manner intended to mimic the burst discharges of the CA1 pyramidal and dentate granule cells, known to be the theta generator zones in the hippocampus, elicits a robust LTP in field CA1 when these bursts are applied at 5 Hz (Lynch, Muller, Seubert, & Larson, 1988). The important implication arising, first, from this role for theta activity in the in vivo induction of LTP and, second, from the finding that LTP is impaired after inescapable shock is the prediction that inescapable shock will differentially modulate the expression of theta activity in the hippocampus compared with escapable shock. At issue is whether the reported in vitro changes in hippocampal activity could offer an in vivo mechanism for the learning deficits found after inescapable shock. The present study examined the effects of inescapable shock, in relation to escapable shock, on the expression of hippocampal theta activity using the treatment parameters typically used in demonstrating learned helplessness effects.

Method Subjects and Surgery Fifteen male Wistar rats that weighed between 250 and 300 g were, after 1 week of handling, anaesthetized (ketamine, 100 mg/kg im, and xylazine, 2 mg im) and chronically implanted unilaterally with a cannula (22 gauge; Plastics One, Roanoke, VA) aimed 1 mm above the lacunosum moleculare layer of the hippocampus. The coordinates, in relation to bregma, midline, and skull surface, were 4.8 mm (P), 1.8 mm (L), 1.8 mm (V), respectively (Paxinos & Watson, 1986). Cannula dislodgement compromised electrode position in 2 subjects that were, as a consequence, discarded from the study. Histology, conducted 1 week after the end of testing, revealed that in 12 subjects the cannula position was just dorsal of the alveus hippocampus. In 1 inescapable-shock subject, the cannula was located slightly ventral of this region. However, the amplitide of theta activity measured before pretreatment from this subject was between 760 and 800 jtV, and so any alterations in theta activity after shock treatment would still have been detected. Apparatus The electrode and recording assembly were comprised of a pair of 100-nm platinum-iridium electrodes, insulated to within 0.25 mm of the tip, implanted in a staggered formation with the tips 0.5 mm apart with the noninverting (positive) electrode aimed above and the inverting (negative) electrode below the CA1 pyramidal cell layer. The electrode mount was secured with screws to the cannula once in place. Signals were amplified and bandpass filtered (3dB

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points; 0.2 Hz and 30 Hz) and sampled at 100 Hz by an analogdigital converter (Maclab, Analogue Digital Instruments, Aukland, New Zealand) connected with a Macintosh SE containing dedicated software to store, display, and analyze the data. The pretreatment stage was conducted in identical shuttle boxes each comprising two compartments (30.5 cm long, 11 cm wide, and 14.5 cm high) joined on a central axis containing an access door (7.5 x 12.75 cm). The axis allowed the apparatus to tilt slightly with the rat's weight to operate a microswitch signaling a completed shuttle. The compartments had grid floors of steel bars each 6 mm in diameter and positioned 1.7 cm apart from center to center. During pretreatment, an alternating-current shock was delivered through the grid floor using a Coulboum shock generator and scrambler at a constant current of 0.6 mA, pulsed at a frequency of 50 Hz. During EEG recording sessions, subjects were placed in Plexiglas Skinner boxes (20 cm long, 20 cm wide, and 24 cm high) positioned over a grid floor. The grid floor could move independently of the box and was secured to a stabilometer that allowed concurrent motor activity measures to be taken throughout the recording sessions. Shock delivered during recording sessions used the same parameters as pretreatment. Procedure After recovery from surgery, the staggered bipolar recording electrodes were lowered through the cannula until the optimum field response was recorded. When theta activity was observed, the cannulas were secured, and note was taken of the amplitude. All implants revealed theta activity with amplitudes ranging from 720 to 1250 liV. Subjects were rank ordered on the basis of theta amplitude and blocked into three groups designated by pretreatment shock condition: no shock (n = 3), escapable shock (« — 5), and inescapable shock (n = 5). During pretreatment, subjects were placed in the shuttle boxes and, in the shock groups, exposed to one session of 80 shock trials with an average intertrial interval of 60 s (range = 30-90 s). Escapable-shock subjects could terminate the shock by performing a oneway shuttle response. Inescapable-shock subjects could not escape, were each yoked to an escapable-shock subject, and received the same number, duration, and pattern of shocks as that subject. The no-shock group was exposed to the pretreatment apparatus but received no shock. Twenty-four hours after the pretreatment shock session, subjects were returned to the recording apparatus, and EEG records were again taken. This recording session lasted for 30 min. After the first 15-min segment, a single 5-s probe shock was administered in the recording apparatus, and EEG recording was continued for another 15-min segment.

Results After 80 trials, the escapable-shock group's average escape latency had declined significantly, f(4) = 16.003, p < .01, as measured from the average of the first 20 trials to the average of the last 20 trials (11.8-5.4 s), which indicated acquisition of this response. At the outset, it was predicted that the effects of inescapable shock on hippocampal EEG would occur mainly within a narrow frequency band (around 5 Hz). Accordingly, the EEG for each subject was transformed, using a Fast Fourier Transformation (FFT algorithm), and blocked into four bands (range = 1-3.9 Hz, 4-7.9 Hz, 8-11.9 Hz, and 12-30 Hz) for statistical comparison between groups. Six-second epochs of EEG

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data were analyzed into spectra 0.5 Hz wide. For the statistical analyses, power for each subject was averaged over 10 separate FFTs and within each frequency band into an overall mean power for each minute of the recording session. During the first 15-min recording segment, no effect of the pretreatment on EEG was detected between groups (Figure la, left panel). An analysis of variance (ANOVA; Group x Time) of the FFT data indicated that there were no differences between groups in any frequency band (F < 1 in each case). No Group x Time interactions were significant (p > .05 in each case), although there was a general decline in power over this recording segment indicated by a significant time effect in the 1-3.9-Hz block, F(14, 140) = 3.45, p < .01, the 4-7.9-Hz block, F(\4, 140) = 5.01, p < .01, and the 8-11.9-Hz block, F(14, 140) = 2.13, p < .05. This pattern of results was also found in the activity data (Figure Ib, left panel). Again, an ANOVA detected neither a significant main effect of groups nor an interaction (p > .05 in both cases), although motor activity generally declined over this recording segment, F(14, 140) = 3.77, p < .01. After the probe shock, however, a very different pattern of results emerged (Figure la, right panel). The most obvious difference between the groups was in the occurrence of theta activity. After offset of the probe shock, sustained trains of theta activity, accompanied by immobility, were observed in all subjects in both the no-shock and escapable-shock groups, whereas no theta activity was observed in the inescapable-shock group despite the same initial degree of immobility (Figure Ic). Indeed, no inescapably shocked subject produced theta activity at any time during the 15-min recording segment after the probe shock. This qualitative difference between the number of subjects that showed theta activity in the inescapable-shock group and in the other two groups was confirmed using a chi-square statistic, x20) = 9.32, p < .01, two-tailed. FFT of the EEG data established that the theta activity elicited by the probe shock in the escapable- and no-shock groups was predominantly in the 4-7.9-Hz band (Figure la). Further, an ANOVA indicated a difference between groups in this frequency band, F(2, 10) = 54.62,p< .01,confirming the qualitative difference observed in the EEG data just noted. Post hoc Newman-Keuls tests, conducted on the averaged group FFT data, revealed that, although there was no difference between the no-shock and escapable-shock groups (p > .05), both of these groups differed from the inescapableshock group (p < .01 in both cases). A significant effect of group was also detected in the analysis of the FFT data in the 1-3.9-Hz band, F(2, 10) = 7.30, p< .05. Post hoc Newman-Keuls tests indicated that spectral power in both the escapable- and inescapable-shock groups was elevated compared with the no-shock group in this frequency band (p < .05 andp < .01, respectively), suggesting an effect of pretreatment shock per se. This effect of pretreatment was, however, greater in the inescapable group than in the escapable group (p < .05). Although unpredicted, this finding is explicable because an often observed effect of this regime of shock treatment is enhanced analgesic responsiveness (Maier & Keith, 1987), an effect known to increase lowfrequency EEG activity (Soulairac, Gottesmann, & Char-

pentier, 1967). The fact that this effect of shock treatment was greater in the inescapable-shock group than in the escapable-shock group accords with behavioral observations in other studies (Jackson et al., 1979). No other pairwise comparisons of the FFT data were significant. An ANOVA did not detect an overall groups effect on motor activity after the probe shock, F(2, 10) = 1.03, p > .05, although activity did generally increase over this segment, F(14, 140) = 2.29, p < .01. It should be noted, therefore, that the main effect on EEG activity in the 4-7.9-Hz band is unlikely to have been caused by a differential effect of pretreatment on motor activity. Theta activity recorded during periods of exploratory motor activity has been dissociated both pharmacologically and physiologically from theta activity recorded during periods of immobility, and these two types of theta activity have subsequently been labeled Type 1 and Type 2, respectively (Bland, 1986). The theta activity recorded during the second recording segment in the present study was confined to periods of immobility and thus suggests a difference in the expression of Type-2 theta activity between groups. To examine this possibility more closely, a ratio was calculated for each subject between the number of seconds of theta activity during immobility and the number of seconds of immobility for each of the first 5 min of the second recording segment. These data are presented in Figure 2. It is clear that, although the number of seconds of immobility in each minute did not differ significantly between groups, there was a clear difference in the number of seconds of theta activity recorded during these periods of immobility. Mann-Whitney U tests (used because of heterogeneity of variance considerations) revealed that, although the escapable- and no-shock groups did not differ on this measure (V = 10, p > .05), both displayed significantly more theta activity during periods of immobility than the inescapable-shock groups (U = 0, p < .01, two-tailed).

Discussion The main finding of the present study was that exposure to inescapable footshock, adequate for the induction of learned helplessness effects, specifically inhibited hippocampal function when subjects were subsequently challenged with a similar stressful event. This suppressive effect was found primarily in hippocampal theta activity within a narrow frequency band (4-7.9 Hz). The theta activity of animals either not previously stressed or subjected to escapable stressors was not suppressed in this way, and long trains of theta activity during immobility were elicited by the probe shock. Interestingly, a difference between the groups was only detected after challenge with a probe shock, suggesting that there was no general alteration in the EEG of the inescapableshock subjects. These results add to suggestions that there is a relationship between the effects of stressors and hippocampal function (Gray, 1982; Shors et al., 1989). Further support for this proposal may be taken from recent reports that both a noxious heat stimulus applied to the tail (Khanna & Sinclair, 1989) and inescapable footshock (Henke, 1990) induce pro-


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Figure I. Electroencephalographic records were taken 24 hr after shock in a 30-min session divided into two 15-min recording segments. (The segments were separated by a single 5-s probe shock, [a] The frequency data [in hertzl from the two 15-min segments are averaged into three 5-min epochs and plotted against spectral power.)

longed depressive effects on population spikes in area CA1 and the dentate granule cells, respectively. Because both the CA1 and dentate areas are theta generator zones in the hippocampus, there is likely to be a close relationship between the way these effects of stress and those reported in the present study arc mediated. One important link in this regard is the finding that the presence of monoamines in the hippocampus both excites dentate granule cell activity and is a necessary condition for LTP (Bliss, Goddard, & Riives, 1983). Because inescapable-shock, but not escapable-shock, is known to severely deplete brain monoamines (Anisman et al., 1979; Weiss et al., 1981), this may suggest a mechanism for the modulation of hippocampal activity by stress. Further, the depletion of monoamines in the medial septum is known to antagonize hippocampal cholinergic activity (Costa, Panula, Thompson, & Cheney, 1983), an effect that may directly

impair Type-2 theta activity in subjects exposed to inescapable shock because there is evidence to suggest that this type of theta activity is cholinergically mediated (Bland, 1986). Interestingly, if this latter mechanism is found to underlie the effects on hippocampal activity observed in the present study, it may suggest a relationship between the effects of inescapable shock and the interference observed in learning and memory tasks after treatments that depress cholinergic activity (Marighetto, Durkin, Toumane, Lebrun, & Jaffard, 1989; Sara, 1989). Although this analysis points toward an in vivo mechanism for learned helplessness effects, its convergence with similar effects of inescapable shock on LTP also adds strength to proposals that theta activity is involved in the in vivo induction of LTP. Some recent evidence suggests, however, that theta activity plays only a modulatory role in the in-

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Figure 1 (continued). Electroencephalographic records were taken 24 hr after shock in a 30-min session divided into two 15-min recording segments. (The segments were separated by a single 5-s probe shock, [b] The motor activity for each recording segment is plotted separately as counts, [c] After the probe shock in the second segment, trains of theta activity were observed in the no-shock [N-S] and escapable-shock [E-S] groups but not in the inescapable-shock group [I-S]. Representative records are presented for a subject from each group for the first 6 s of immobility observed after the probe shock. Rhythmic slow-wave activity [theta] is clearly visible in the N-S and E-S records, and its absence may also be observed in the record from the I-S subject, which is predominantly largeamplitude irregular activity.)

duction of LTP; it has been reported that timing the eliciting tetanus to accompany the positive phase of the theta rhythm induces robust LTP, whereas timing these bursts to the negative phase has either a depressive or no effect (Pavlides, Greenstein, Grudman, & Winson, 1989). There are reports that, in vivo, bursts of action potentials in the dentate gyrus fire in phase with theta rhythm in just this way (Fox, Wolfson, & Ranck, 1983; Rose, 1983), suggesting that theta activity, rather than directly eliciting LTP, may be acting to entrain the activity of single units perhaps through the depolarisation of W-methyl-D-aspartate receptors (Gustafsson, Wigstrom, Abraham, & Huang, 1987; Morris, 1989). Although it has been reported that trains of Type-2 theta activity seldom occur spontaneously in the rat, Type-2 theta activity is consistently elicited in response to mildly aversive stimuli such as 50 °C heat (Khanna & Sinclair, 1989), the brief shock exposures during aversive Pavlovian conditioning (Sainsbury, Harris, & Rowland, 1987; Whishaw, 1972), tail pinch (Stewart & Vanderwolf, 1987), and the distal lo-

cation of a natural predator (Sainsbury, Heynan, & Montoya, 1987). Theta activity is not, however, observed with more intense stimuli such as 55 °C heat (Khanna & Sinclair, 1989) and the proximal presentation of a predator (Montoya, 1988). It may thus be the case that the expression of theta activity during periods of immobility in the rat is dependent on arousal within a specific range with both sub- and suprarange levels of arousal inhibiting theta activity and perhaps other hippocampal functions. The results of the present study are consistent with this hypothesis following recent suggestions that escapable- and inescapable-shock are differentially arousing with inescapable shock eliciting intense chronic anxiety and escapable shock having a more moderate and acute effect (Minor, Trauner, Lee, & Dess, 1990). Two general implications arise from the present study. First, although the escapable-shock group was exposed to the same intensity and pattern of shock as the inescapable-shock subjects, these subjects did not show a suppression of theta activity in relation to unshocked controls. The difference

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Figure 2. The ratio calculated between the number of seconds of theta activity during immobility and the total number of seconds of immobility is presented by group for each minute over the first 5 min after the probe shock (± 1 SEM). (The upper portion of the figure clearly shows the suppression of theta activity in the inescapable-shock group in relation to both the escapable- and no-shock groups. The lower portion illustrates that this difference occurred in the absence of a difference between groups in the number of seconds of immobility over each minute [± 1 SE^,)

between the effects of controllable and uncontrollable stress supports proposals that psychological factors, such as the detection of event contingencies, can have fundamental electrophysiological effects. Second, although it is possible that theta activity plays only a modulatory role in learning processes involving the hippocampus, to the extent that correlations reported between tbeta activity and associative learning indicate a causal relationship, the present findings suggest that the learning deficits observed after inescapable shock are based on changes in hippocampal function. Findings from studies using the hippocampal slice preparation to examine LTP have led to similar conclusions (Shors et al., 1989), although the important contribution of the present study is that this result has been established in vivo using those procedures typically used to induce learned helplessness effects. References Anisman, H., Remington, G., & Sklar, L. S. (1979). Effects of inescapable shock on subsequent escape performance: Catecholaminergic and cholinergic mediation of response initiation and maintenance. Psychopharmacology, 61, 107-124. Balleine, B. W., McGregor, I. S., & Atrens, D. M. (1989). Control-

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Winson.J. (1978). Patterns of hippocampaltheta rhythm in the freely moving rat. Electroencephalography and Clinical Neurophysiology, 36, 291-301. Received April 25, 1990 Revision received June 19,1990 Accepted August 20, 1990 •