Behavioral Neuroscience 2004, Vol. 118, No. 5, 1123–1127
Copyright 2004 by the American Psychological Association 0735-7044/04/$12.00 DOI: 10.1037/0735-7044.118.5.1123
Effects of Exercise on Pavlovian Fear Conditioning David E. Baruch, Rodney A. Swain, and Fred J. Helmstetter University of Wisconsin—Milwaukee Exercise promotes multiple changes in hippocampal morphology and should, as a result, alter behavioral function. The present experiment investigated the effect of exercise on learning using contextual and auditory Pavlovian fear conditioning. Rats remained inactive or voluntarily exercised (VX) for 30 days, after which they received auditory-cued fear conditioning. Twenty-four hours later, rats were tested for learning of the contextual and auditory conditional responses. No differences in freezing behavior to the discrete auditory cue were observed during the training or testing sessions. However, VX rats did freeze significantly more compared to controls when tested in the training context 24 hr after exposure to shock. The enhancement of contextual fear conditioning provides further evidence that exercise alters hippocampal function and learning.
neurotrophic factor (BDNF) mRNA in brain regions implicated in learning, such as the hippocampus (Neeper et al., 1995, 1996). BDNF is believed to contribute to synaptic transmission and plasticity (Lu & Chow, 1999), and contextual fear conditioning, a type of hippocampus-dependent learning (Kim & Fanselow, 1992), coincided with increased expression of BDNF (Hall, Thomas, & Everitt, 2000). Pavlovian fear conditioning involves the pairing of a novel environment or tone (conditional stimulus; CS) with a noxious stimulus (unconditional stimulus; UCS) that results in conditional fear responses. Through this CS–UCS pairing, the rat exhibits freezing behavior, a species-specific defense response, following exposure to the CS. The hippocampus has been shown to contribute selectively to contextual, but not auditory, fear conditioning (Kim & Fanselow, 1992; Phillips & LeDoux, 1992) by supporting processes that form a representation of the features that make up the context (Rudy & O’Reilly, 2001). Although evidence suggests a relationship between voluntary exercise and hippocampal function, no study has directly investigated the effect of exercise on contextual fear conditioning. In the present study, rats were given access to running wheels in their home cages or remained inactive. After 30 days, all rats underwent fear conditioning to both the context and an auditory CS, and on the following day were tested for both contextual and auditory conditional fear responses. A robust exercise-related enhancement in contextual, but not auditory, conditioning would provide additional support for the notion that exercise facilitates neural plasticity in the hippocampus and facilitates learning.
Physical activity in animals has been shown to produce a wide variety of morphological changes in the central nervous system, including angiogenesis in the cerebellum (Isaacs, Anderson, Alcantara, Black, & Greenough, 1992) and primary motor cortex (Swain et al., 2003) and increased expression of neurotrophins in the hippocampus, caudal and frontal cortex, and cerebellum (Neeper, Gomez-Pinilla, Choi, & Cotman, 1995, 1996). In addition, exercise has been found to increase the density of dopamine receptors in the striatum (Gilliam et al., 1984) and overcome age-related reductions in hippocampal muscarinic receptor density (Fordyce, Starnes, & Farrar, 1991). Exercise has also been reported to facilitate learning in a wide variety of hippocampus-dependent tasks such as the Morris water maze (Fordyce & Farrar, 1991a, 1991b; Fordyce & Wehner, 1993; Van Praag, Christie, Sejnowski, & Gage, 1999), the radial-arm maze (Anderson et al., 2000), and passive avoidance conditioning (Radak et al., 2001; Samorajski et al., 1985). Several studies demonstrated plastic changes specific to the hippocampus following exercise. For example, exercise promoted neuron proliferation and survival (Van Praag, Kempermann, & Gage, 1999), induced expression of neurotrophic factors (Gomez-Pinilla, Dao, & So, 1997; Neeper et al., 1995, 1996), modulated gene expression important for general neuronal structure and function (Tong, Shen, Perreau, Balazs, & Cotman, 2001), and facilitated long-term potentiation (LTP; Van Praag, Christie, et al., 1999). Voluntary exercise has provided a means to measure the effects of exercise without potential confounds that result from forced exercise (Moraska, Deak, Spencer, Roth, & Fleshner, 2000). Voluntarily exercised animals have demonstrated enhanced learning (Anderson et al., 2000; Samorajski et al., 1985; Van Praag, Christie, et al., 1999), and increased expression of brain-derived
Subjects
David E. Baruch, Rodney A. Swain, and Fred J. Helmstetter, Department of Psychology, University of Wisconsin—Milwaukee. This work was supported by National Institutes of Health Grant MH061450 to Fred J. Helmstetter. Correspondence concerning this article should be addressed to Rodney A. Swain, Department of Psychology, University of Wisconsin, P.O. Box 413, Milwaukee, Wisconsin 53201. E-mail:
[email protected]
Twenty adult male Long–Evans hooded rats (Harlan, Madison, WI) weighing 300 –350 g were used. Ten were randomly chosen to occupy cages that allowed free access to a running wheel (voluntary exercise condition, VX), and the remaining 10 were housed individually in hanging stainless steel cages (inactive control condition, IC). All rats had unrestricted access to food and water. The colony room was kept at a constant temperature of 21.1 °C and scheduled on a 12:12-hr light– dark cycle. Each conditioning session occurred during the light portion of the cycle. All rats were handled for 3 days prior to fear conditioning.
Method
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Apparatus Two types of running wheels were used. Five of the running wheels operated with a mechanical counter that produced a clicking noise (approximately 61 dB and 85 ms in duration) after each revolution (Type A). Type A wheels were 35 cm in diameter, weighed an average of 935 g, and were adjacent to the 23.5 cm ⫻ 45.0-cm cage. Rats entered the running wheel through an 11-cm diameter cylinder that connected the running wheel to an opening made on the narrow side of the cage. The other five running wheels used a magnetic counter that determined the number of wheel revolutions produced (Type B). Type B wheels, 34.5 cm in diameter and weighing an average of 1,690 g, were positioned directly in the cage with the rat. Fear conditioning and subsequent testing occurred in two contexts. Context A comprised four identical Plexiglas and stainless steel observation chambers (28 cm long ⫻ 20.5 cm high ⫻ 21 cm wide) placed inside four wooden, sound-attenuating chests. Each chamber was connected to a Model 700 Grason-Stadler shock generator (West Concord, MA). A scrambled AC current was delivered through a grid floor that consisted of 18 stainless steel rods that were 5 mm in diameter and spaced 12 mm apart. A speaker (9.5 cm in diameter; 8 ⍀, 4 W) was mounted inside each chamber and connected to a Model 901 B Grason-Stadler white noise generator. Each chamber included a ventilation fan that produced a 60 – 65-dB background noise. A 5% ammonium hydroxide solution was used to clean the chambers between each conditioning session in order to mask the odor of other rats. Each wooden chest was illuminated overhead by a white light (7.5 W) and contained a transparent Plexiglas door that allowed recording of behavior. Context B consisted of four identical chambers that differed in room location, floor configuration, geometric design, and odor compared to Context A. One Plexiglas panel covered the stainless steel grid floor, and another Plexiglas panel was inserted so that one wall slanted at approximately a 45° angle. The chambers were illuminated by a 7.5-W white light and placed inside a sound-attenuating wooden chamber. A speaker (9.5 cm in diameter, 8 ⍀, 4 W) was mounted inside each chamber and connected to a Model 901 B Grason-Stadler white noise generator. Each chamber included a ventilation fan that generated a 54 –58-dB background noise and was cleaned with a 1% acetic acid solution between each session in order to mask the odor of other rats and to differentiate the two contexts with distinct olfactory cues.
Procedure The rats were housed in cages with running wheels or in standard home cages for 30 days. Each morning, an experimenter recorded the number of wheel revolutions the rats completed during the previous day. On the 31st day, the rats were placed in the conditioning chambers (Context A) for training. They were allowed to explore the context undisturbed for 6 min, after which they received four white noise CS presentations (72 dB, 10 s) that coterminated with a foot shock UCS (1 mA, 1 s). Each white noise– shock pairing was separated by a 90-s intertrial interval. After the final shock, rats remained in the chambers for an additional 4 min and were then returned to their home cages. Twenty-four hours later, the rats were tested to the contextual CS in Context A and to the white noise CS in the novel Context B in order to distinguish conditional responses resulting from contextual or discrete (i.e., white noise CS) cues. The order in which the rats were tested was counterbalanced so that half of the rats from each group were tested first in Context A and the remaining were tested in the novel Context B and then returned to their home cages. Two hours later, the rats previously tested in Context A were tested in Context B, and vice versa. Context testing occurred in Context A and consisted of exposing rats to the context in which they were trained for 15 min, with no discrete CS or shock UCS presentation. White noise cued testing in Context B consisted of exposure to the novel context for 6 min, followed by a 5-min white noise
CS (72 dB) presentation in the absence of any shock UCS. The rats remained in the chambers an additional 4 min after the termination of the white noise CS and were then returned to their home cages. During training and testing sessions, an observer blind to treatment conditions scored the behavior of each rat, every 4 s, as either freezing or active. The percentage of time freezing was used as an index of conditional fear in response to stimuli associated with shock. Freezing was defined as the complete absence of movement except that necessary for respiration, and all other forms of behavior were categorized as active (Fanselow, 1980).
Results Running Wheel Examination of the running wheel data indicated that rats in Type A wheels ran an average of 2,459.62 wheel rotations per day, whereas those in Type B ran 4,932.93 rotations per day. A oneway, repeated measures analysis of variance (ANOVA) using wheel type (A or B) as the independent variable and number of wheel rotations ran per day (1–30) as the dependent measure tested whether there was a statistically reliable difference in running performance between rats housed with the two wheel types. The results indicated that rats with access to Type B wheels ran significantly more than those with access to Type A wheels across the entire 30 days, F(1, 8) ⫽ 5.487, p ⬍ .05. A significant main effect of time, F(29, 232) ⫽ 12.281, p ⬍ .001, but no interaction, F(29, 232) ⫽ 0.806, p ⬎ .05, was found. There were no group differences, however, by the final day, F(1, 8) ⫽ 2.043, p ⬎ .05. Most important, a one-way ANOVA using wheel type (A or B) as the independent variable and percent time freezing as the dependent variable found no significant freezing difference between rats that ran in Type A or B during the training or testing sessions. Consequently, all rats housed with running wheels were collapsed into one group for further analysis.
Training The data from the training session was analyzed in three periods: baseline, CS–UCS pairings (including the intertrial intervals), and postshock (consisting of the 4 min that followed the final footshock). Separate ANOVAs using group (VX or IC) as the independent variable and percent time freezing as the dependent variable were conducted for each period. The results, depicted in Figure 1a, indicate there were no significant group differences during the baseline, CS–UCS pairings, or postshock period, F(1, 18) ⫽ 0.155, p ⬎ .05; F(1, 18) ⫽ 1.815, p ⬎ .05; F(1, 18) ⫽ 2.641, p ⬎ .05, respectively. Thus, VX rats did not significantly differ during training compared to IC rats, indicating that voluntary exercise failed to significantly facilitate performance during the initial acquisition of a fear-evoked conditional response. The “activity burst,” a measure of the unconditional response elicited by the shock UCS (Fanselow, 1984), was analyzed to assess possible changes in shock sensitivity resulting from exercise. Activity burst duration was defined by the mean number of active behaviors sampled every 4th second during the intertrial intervals (defined here as the 90-s period that followed each of the four UCS footshocks) beginning from the shock offset until the first two successive freezing responses. A repeated measures ANOVA was conducted with group (VX or IC) as the independent
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Cued Test Auditory fear conditioning was analyzed in three periods: baseline, white noise CS presentation, and post-CS period. There were no significantly reliable differences during the baseline period that preceded the white noise presentation, F(1, 18) ⫽ 1.503, p ⬎ .05. Furthermore, no group differences in freezing were demonstrated by analyses of the white noise CS, F(1, 18) ⫽ 0.240, p ⬎ .05 (Figure 1b), or during the post-CS period, F(1, 18) ⫽ 0.180, p ⬎ .05.
Discussion
Figure 1. A: Mean (⫾ SEM) percent freezing during the baseline, conditional stimulus– unconditional stimulus (CS–UCS) pairings, and postshock training periods. Voluntary exercise (VX) and inactive control (IC) rats displayed similar levels of freezing during the training session. B: Mean percent freezing during the 15-min context test 24 hr posttraining, and the 5-min white noise presentation in a novel context 24 hr posttraining. VX rats exhibited enhanced levels of freezing compared to IC rats when exposed to the contextual, but not the auditory, CS. **p ⬍ .01.
variable and the mean number of active samples during the four intertrial intervals as the dependent measure. No significant main effect for group was observed, F(1, 18) ⫽ 3.796, p ⬎ .05. In addition, there was no significant main effect for intertrial interval or interaction, F(3, 54) ⫽ 0.391, p ⬎ .05; F(3, 54) ⫽ 0.177, p ⬎ .05, respectively. Accordingly, it can be inferred that shock sensitivity throughout training was similar between VX and IC rats.
Context Test Contextual fear conditioning was assessed by averaging the total amount of time spent freezing across the 15-min session. Freezing to the contextual CS, shown in Figure 1b, revealed that VX rats froze significantly more than IC rats, F(1, 18) ⫽ 13.116, p ⬍ .01. This significant increase in VX freezing performance during context testing suggests that voluntary exercise enhanced learning of context-evoked fear.
The results of this experiment indicate that voluntary exercise facilitated contextual fear conditioning. These findings extend previous reports of improved learning in hippocampal tasks following voluntary physical activity (Anderson et al., 2000; Samorajski et al., 1985; Van Praag, Christie, et al., 1999). The enhancement of contextual, but not auditory, fear conditioning suggests that the facilitatory effect of exercise may be specific to the hippocampus. It is important to note that although the apparently selective enhancement of contextual conditioning seen here may be due to modification of hippocampus-dependent processing by exercise, it may also partially reflect an unequal sensitivity to group differences when comparing contextual versus auditory CS performance. During the test presentation of the auditory CS conducted outside the original training context, animals in both groups were freezing approximately 70% of the period. Net levels of freezing during the context test tended to be lower. It is therefore possible that the differential outcomes seen here may reflect a differential sensitivity of the two tests or a “ceiling effect” in tone performance that masks a potential parallel enhancement in VX rats. Although this is possible, it should be noted that using our assessment procedures, auditory CS performance can be resolved over the full range of the measure (i.e., rats can freeze 100% of the time given appropriate training conditions). It should also be noted that even if an enhancement of conditioning to the tone CS was present but was masked by a performance ceiling in this experiment, this would still support the more general conclusion that voluntary exercise facilitates learning. Previous research has focused on the enhancement of Morris water maze learning, in rats and mice, subsequent to both voluntary and forced exercise (Fordyce & Farrar, 1991a, 1991b; Fordyce & Wehner, 1993; Van Praag, Christie, et al., 1999). Correlating exercise and improved learning by means of the Morris water maze task may be complicated by the potential effect of exercise on motor activity. However, exercised animals have also demonstrated enhanced learning in the radial-arm maze task (Anderson et al., 2000) and exhibited longer latencies (better performance) in a passive avoidance task (Radak et al, 2001; Samorajski et al., 1985). In addition, physical activity selectively enhanced spatial, but not nonspatial—and thus hippocampus-independent—versions of the Morris water maze task (Fordyce & Wehner, 1993). Taken together, the above findings, along with the improved contextual fear conditioning reported in the present study, support the idea that exercise enhances learning in a number of hippocampusdependent tasks. Although the present study does not directly address the effects of exercise on hippocampal plasticity, the observed facilitation of
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behavioral performance is consistent with such an effect. As previously described, exercise promotes neurogenesis and the expression of trophic factors, including BDNF, nerve growth factor, and fibroblast growth factor-2 in the hippocampus (Gomez-Pinilla et al., 1997; Neeper et al., 1995, 1996; Tong et al., 2001; Van Praag, Christie, et al., 1999; Van Praag, Kempermann, & Gage, 1999). Specifically, BDNF mRNA was found to be most highly expressed in the mouse hippocampus (Hofer, Pagliusi, Hohn, Leibrock, & Barde, 1990) and up-regulated at higher levels than other closely related trophic factors after exercise (Neeper et al., 1996; Tong et al., 2001). In parallel with findings suggesting a role for BDNF in hippocampal plasticity are reports indicating a BDNF involvement in learning. Hall et al. (2000) reported that induction of BDNF mRNA occurred in the hippocampus during contextual fear conditioning. Moreover, injection of BDNF antisense oligonucleotides into the hippocampus impaired retention of passive avoidance conditioning in rats and inhibited hippocampal LTP (Ma, Wang, Wu, Wei, & Lee, 1998). Nevertheless, intracerebroventricular infusions of NGF, neurotrophin 3 and 4/5 reversed water maze learning impairments in aged-rats, but BDNF infusions did not (Fischer, Sirevaag, Wiegand, Lindsay, & Bjorklund, 1994). Current findings therefore suggest that BDNF may be a necessary factor in learning that works in parallel with other contributing factors. Alterations in hippocampal theta rhythm, slow waves that oscillate between 2 and 8 Hz, resulting from exercise might also have contributed to the enhanced learning of contextual fear. Theta rhythm closely correlates with physical behaviors (Bland, 1986), including running wheel behavior (Oddie, Stefanek, Kirk, & Bland, 1996). Theta rhythm rates have been reported to increase in parallel with enhanced induction of hippocampal LTP in waterdeprived rats (Maren, DeCola, Swain, Fanselow, & Thompson, 1994). Notably, rats in the same experiment demonstrated enhanced contextual conditioning. In addition, water-deprived rabbits that showed more rapid acquisition of nictitating membrane conditioning also demonstrated a correspondingly higher proportion of theta rhythm (Berry & Swain, 1989). Siedenbecher, Laxmi, Stork, and Pape (2003) recently implicated theta rhythm as a possible mode of communication between the lateral amygdala (LA) and CA1 subfield of the hippocampus during retrieval of conditional fear. The theta rhythm was found to be synchronized in the LA and CA1 upon exposure to contextual CSs. It may be possible that such a pathway was facilitated by exercised-induced increases in synchronization of hippocampal theta rhythms and thus factored into the enhanced contextual fear conditioning reported in this study. Similar activity burst durations between groups suggests that differences in shock sensitivity did not contribute to the enhancement of contextual fear conditioning. However, other factors not directly related to learning or cognitive function could potentially account for the present findings. Exercise has been reported to attenuate certain stress-related responses (e.g., Mills & Ward, 1986). It is therefore possible that the facilitatory effect of exercise on learning reported here was not due directly to hippocampal modification, but rather to the modification of stress-related reactions that normally compete with learning in this paradigm. If exercise-related learning facilitation were simply due to general reduction of stress, then in the present study both contextual and auditory fear conditioning should have been equally enhanced.
The present study provides further evidence that exercise facilitates hippocampal function and implicates potential roles for neurogenesis, neurotrophic expression, and theta rhythm in learning and memory. Certainly, more direct manipulations of these possible mechanisms for hippocampal plasticity as assessed through diverse hippocampal tasks must be conducted. Moreover, it is necessary to identify the effect of exercise on nonhippocampal tasks in order to better characterize the manner in which exercise modulates general learning. In future experiments, this could be accomplished with auditory fear conditioning designed to promote less fear than observed in the present experiment. Finally, it would be beneficial to delineate more precisely the time course during which exercise exerts its facilitatory effect on hippocampal learning.
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Received October 29, 2003 Revision received February 19, 2004 Accepted March 19, 2004 䡲
