Glucocorticoid enhancement of dorsolateral striatum-dependent habit memory requires concurrent noradrenergic activity

Neuroscience 311 (2015) 1–8

GLUCOCORTICOID ENHANCEMENT OF DORSOLATERAL STRIATUM-DEPENDENT HABIT MEMORY REQUIRES CONCURRENT NORADRENERGIC ACTIVITY Key words: corticosterone, propranolol, stress, memory, striatum, habit.

J. GOODMAN, K.-C. LEONG AND M. G. PACKARD * Department of Psychology and Institute for Neuroscience, Texas A&M University, United States

INTRODUCTION Abstract—Previous findings indicate that post-training administration of glucocorticoid stress hormones can interact with the noradrenergic system to enhance consolidation of hippocampus- or amygdala-dependent cognitive/emotional memory. The present experiments were designed to extend these findings by examining the potential interaction of glucocorticoid and noradrenergic mechanisms in enhancement of dorsolateral striatum (DLS)-dependent habit memory. In experiment 1, different groups of adult male Long–Evans rats received training in two DLS-dependent memory tasks. In a cued water maze task, rats were released from various start points and were reinforced to approach a visibly cued escape platform. In a response-learning version of the water plus-maze task, animals were released from opposite starting positions and were reinforced to make a consistent egocentric body-turn to reach a hidden escape platform. Immediately post-training, rats received peripheral injections of the glucocorticoid corticosterone (1 or 3 mg/kg) or vehicle solution. In both tasks, corticosterone (3 mg/kg) enhanced DLS-dependent habit memory. In experiment 2, a separate group of animals received training in the response learning version of the water plus-maze task and were given peripheral post-training injections of corticosterone (3 mg/kg), the b-adrenoreceptor antagonist propranolol (3 mg/kg), corticosterone and propranolol concurrently, or control vehicle solution. Corticosterone injections again enhanced DLS-dependent memory, and this effect was blocked by concurrent administration of propranolol. Propranolol administration by itself (3 mg/kg) did not influence DLS-dependent memory. Taken together, the findings indicate an interaction between glucocorticoid and noradrenergic mechanisms in DLS-dependent habit memory. Propranolol administration may be useful in treating stress-related human psychopathologies associated with a dysfunctional DLS-dependent habit memory system. Ó 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Stress influences a wide range of learning and memory processes. Neurobehavioral studies employing both lower animals and humans indicate that stress/anxiety can either enhance or impair memory and that the direction of these effects depends in part on the type of memory being investigated (for reviews, see Packard, 2009b; Packard and Goodman, 2012, 2013; Schwabe, 2013). For instance, several studies indicate that stress/ anxiety impairs cognitive/spatial memory mediated by the hippocampus (Luine et al., 1994; Diamond et al., 1996; de Quervain et al., 1998; Kim et al., 2001; Conrad et al., 2004; Wingard and Packard, 2008; Packard and Gabriele, 2009). In contrast, stress or anxiety can enhance stimulus-response habit memory mediated by the dorsolateral striatum (DLS) in both rodents (Packard and Wingard, 2004; Elliot and Packard, 2008; Wingard and Packard, 2008; Schwabe et al., 2008; Hawley et al., 2011; Leong et al., 2012, 2015; Leong and Packard, 2014) and humans (Schwabe et al., 2007, 2008; Schwabe and Wolf, 2009, 2010; Schwabe et al., 2010a, b, 2013; Guenzel et al., 2014). Although the precise mechanisms underlying the mnemonic effects of emotional arousal have yet to be fully characterized, extensive evidence indicates a critical role for stress hormones, including catecholamines (e.g. noradrenaline) and glucocorticoids (corticosterone in rodents; cortisol in humans). Stress hormones released during an emotionally arousing experience may partially modulate memory by activating noradrenergic, glucocorticoid, or mineralocorticoid receptors in several brain areas related to learning and memory (McGaugh, 2004; Roozendaal et al., 2009). Consistent with this hypothesis, the effects of emotional arousal on hippocampus- and DLS-dependent memory can be mimicked following administration of drugs that boost stress hormone activity (Luine et al., 1993; de Quervain et al., 1998; Packard and Wingard, 2004; Medina et al., 2007; Wingard and Packard, 2008; Quirarte et al., 2009; Guenzel et al., 2014). In addition, the mnemonic effects of emotional arousal may be prevented following pharmacological blockade of noradrenergic, glucocorticoid, or mineralocorticoid receptors (Maroun and Akirav, 2008; Schwabe et al., 2009; Schwabe et al., 2010a, 2011b).

*Corresponding author. Address: Department of Psychology, Texas A&M University, College Station, TX 77843, United States. Tel: +1979-845-9504; fax: +1-979-845-4727. E-mail address: [email protected] (M. G. Packard). Abbreviations: DLS, dorsolateral striatum; DMS, dorsomedial striatum; ITI, intertrial interval; LSD, Least Significant Difference. http://dx.doi.org/10.1016/j.neuroscience.2015.10.014 0306-4522/Ó 2015 IBRO. Published by Elsevier Ltd. All rights reserved. 1

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Interestingly, adrenergic and glucocorticoid mechanisms can also interact to influence learning and memory processes. Several studies indicate that the memory-enhancing and impairing effects of glucocorticoid receptor stimulation may be prevented following concurrent administration of adrenoreceptor antagonists such as propranolol, suggesting that the mnemonic effects of glucocorticoids depend on concurrent noradrenergic activity (Quirarte et al., 1997; Roozendaal et al., 2004a,b, 2006b; de Quervain et al., 2007). Studies examining the interaction between adrenergic and glucocorticoid mechanisms have implemented learning and memory tasks that predominantly depend on cognitive and emotional memory processing mediated by the hippocampus, medial prefrontal cortex, and the amygdala (e.g. Quirarte et al., 1997; Roozendaal et al., 2004a, 2006a; de Quervain et al., 2007). There is evidence that stress hormone activity can also enhance stimulus-response/habit memory mediated by the DLS. However, whereas many of these studies have employed drugs targeting the noradrenergic system, relatively few studies have examined whether glucocorticoid administration might similarly facilitate learning in tasks that require DLS-dependent memory processes (Medina et al., 2007; Quirarte et al., 2009; Guenzel et al., 2014). In addition, whether the influence of glucocorticoid administration on learning in a DLSdependent memory task depends on concurrent noradrenergic activity has yet to be examined. The present study examined whether glucocorticoid administration enhances DLS-dependent memory and also whether this enhancement is contingent upon concurrent noradrenergic mechanisms. Experiment 1 employed two DLS-dependent memory tasks. The first task was a cued version of the Morris water maze in which rats were reinforced to approach a visibly cued escape platform. In the second task, rats were trained in a response-learning version of the water plus-maze in which they were released from varying start points and were reinforced to make a consistent egocentric turning response at the maze choice point to reach an invisible escape platform. To examine the influence of glucocorticoid administration on memory in these tasks, animals were given immediate post-training peripheral administration of corticosterone. In order to examine potential glucocorticoid-noradrenergic interactions in DLS-dependent memory, in experiment two different groups of rats were trained in the response version of the plus-maze and received post-training peripheral administration of either corticosterone, the b-adrenoreceptor antagonist propranolol, or concurrent infusions of corticosterone and propranolol.

EXPERIMENTAL PROCEDURES Subjects Subjects were 101 experimentally naı¨ ve Harlan Long– Evans rats (300–400 g). Rats were individually housed in a climate-controlled vivarium with a 12:12-h light–dark cycle (lights on at 7:00 AM) and behavioral procedures

were conducted during the light phase of this cycle. Rats received ad libitum access to food and water. Apparatus Animals were trained in a black circular water maze (1.83 m in diameter, 0.58 m in height) filled to a water level of 20 cm. Water temperature was maintained at 25 °C. A clear Plexiglas escape platform (11 cm  14 cm  19 cm) was located 1 cm below the water level and was moved to different spatial locations of the maze throughout training. In the cued version of the water maze task, a square white flag (4.5 cm per side) was attached to the escape platform. For the water plus-maze task, a clear Plexiglas plusmaze (43 cm in height, 25 cm in arm-width, and 60 cm in arm-length) was inserted into the water maze. Also, an additional piece of Plexiglas was used to block-off the arm opposite to the start arm for each trial (e.g. if the rat started in the S arm, entry to the N arm was blocked). This allowed for a T-maze configuration that could be adjusted between trials. No cue was attached to the platform for the water plus-maze task. The maze apparatus was identical to that used in our previous research (Goodman and Packard, 2014). Drug preparation Corticosterone hydrochloride (1.0 or 3.0 mg/kg) was dissolved in 8% ethanol saline. Corticosterone preparation and dosage were selected based on previous research indicating memory modulatory properties of corticosterone in rats (Quirarte et al., 2009). Peripheral injections of corticosterone were administered sub-cutaneously (s.c.). Propranolol hydrochloride (3 mg/kg) was dissolved in physiological saline and administered intra-peritoneally (i.p). This dose of propranolol was selected based on previous evidence indicating that this dose blocked corticosterone effects on memory (Roozendaal et al., 2006b). Behavioral procedures: experiment 1 Training in a cued version of the water maze was conducted over 1 day (4 trials) using a protocol similar to our previous research (Goodman and Packard, 2014). Previous evidence indicates that learning and memory in the cued water maze is critically dependent on DLS function (Packard et al., 1996; Packard and Teather, 1997; Lee et al., 2008; Goodman and Packard, 2014). For each trial, rats (N = 28) were placed into the water facing the maze wall at varying start points (N, S, E, and W). In addition, the visibly cued escape platform was rotated to a different quadrant of the maze (NE, SW, NW, and SE) for each trial. The platform’s distance (i.e. proximal or distal) and direction (i.e. right or left) relative to the rat’s starting position were counterbalanced across the training trials. Therefore, the swimming path was unique for each of the 4 trials. A trial ended once the animal mounted the escape platform. If an animal failed to find the escape platform within 60 s, the rat was manually guided to it. After mounting the platform,

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the rat remained on the platform for 10 s. After each trial the animal was removed from the platform and placed in an opaque holding container adjacent to the maze for a 30-s intertrial interval (ITI). The latency to mount the escape platform was used as a measure of acquisition. After the four training trials in the cued water maze, rats were immediately injected s.c. with corticosterone (1.0 mg/kg, n = 8; 3.0 mg/kg, n = 10) or vehicle solution (8% ethanol-saline solution, n = 10). Twenty-four hours later, rats were given two drug-free probe trials conducted in a manner identical to initial training. Latency to mount the escape platform was used as a measure of memory. A separate group of rats (N = 22) was trained for 5 days (six trials/day) in a water plus-maze task that requires the use of response learning (Goodman and Packard, 2014; Wingard et al., 2015; for reviews, see Packard, 2009a; Goodman and Packard, in press). For each trial in this ‘‘response” version of the plus-maze task, rats were placed in the start arm of the plus-maze (N or S) facing the maze wall. The start arm sequence across the six trials was NSSNNS on odd training days (i.e. days 1, 3, and 5) and SNNSSN on even training days. When a rat started in the North arm, a transparent escape platform was in the West arm. When the animal started in the South arm, the escape platform was in the East arm. Therefore, regardless of the starting position, subjects were reinforced to make a consistent right bodyturn at the choice point of the T-maze in order to reach the escape platform. A trial ended once the animal mounted the platform. If an animal failed to find the escape platform within 60 s, the rat was manually guided to it. After mounting the platform, a rat remained in the maze for another 10 s. The rat was then removed from the platform and placed in an opaque holding container adjacent to the maze for a 30-s ITI. For each trial, if the rat made an initial full-body entry into the arm that contained the platform, the trial was scored as correct. If the rat made a full body entry into the arm that did not contain the platform, the trial was scored as incorrect. Immediately following training on days 1–3, each rat received a s.c. injection of corticosterone (1.0 mg/kg, n = 6; 3.0 mg/kg, n = 8) or vehicle (8% ethanol-saline solution, n = 8). Rats did not receive injections on days 4–5.

physiological saline and a s.c. injection of 8% ethanolsaline solution. Animals did not receive injections on training days 4–5.

RESULTS Experiment 1

Behavioral procedures: experiment 2

Post-training corticosterone injections enhance memory in the cued water maze. Results from the cued water maze task are depicted in Fig. 1. A two-way repeated measures ANOVA (Group  Trial) computed on latency to find the escape platform on trials 1–4 (i.e. prior to post-training drug injections) revealed a main effect of Trial, (F(3,69) = 28.09, p < 0.05), but no main effect of Group (F(2,23) = 0.5, n.s.). In addition, there was no significant Group  Trial interaction (F(2,23) = 0.03, n.s.). These results suggest that all groups acquired the task and that there were no differences between groups before drugs were administered. Therefore, any subsequent effects of drug may not be readily attributed to group differences in task acquisition occurring prior to drug injections. A two-way repeated measures ANOVA (Group  Probe) was computed to determine the effect of post-training corticosterone administration on latency to find the platform on Probes 1 and 2 (i.e. 24 h after post-training drug administration). A two-way repeated measures ANOVA revealed a significant main effect of Group (F(2, 23) = 5.40, p < 0.05) and a significant main effect of Probe (F(1,23) = 4.32, p < 0.05). There was no significant Group  Probe interaction (F(2,23) = .99, n.s.). A post-hoc Fisher’s Least Significant Difference (LSD) test revealed that rats given 3.0 mg/kg corticosterone displayed lower escape latencies during the probe trials (M = 8.81) relative to animals given vehicle solution (M = 14.85), p < .05. In addition, animals given 3.0 mg/kg corticosterone also displayed lower escape latencies than animals given 1.0 mg/kg corticosterone (M = 16.69), p < .05. There was no difference in escape latencies between animals given 1.0 mg/kg corticosterone and control animals given vehicle solution. Overall, the results indicate that post-training administration of corticosterone dosedependently enhanced DLS-dependent memory in a cued-platform water maze task.

Rats (N = 27) were trained in the response-learning version of the water plus-maze task, using a behavioral procedure identical to that described in experiment 1. Immediately following training on days 1–3, each rat received two injections. Animals in the CORT-VEH group (n = 7) received a s.c. injection of corticosterone (3.0 mg/kg) and an i.p. injection of physiological saline. Animals in the PROP-VEH group (n = 6) received an i.p. injection of propranolol (3.0 mg/kg) and a s.c. injection of 8% ethanol-saline solution (i.e. the vehicle solution used in corticosterone injections). Animals in the CORT-PROP group (n = 7) were given a s.c. injection of corticosterone (3.0 mg/kg) and an i.p. injection of propranolol (3.0 mg/kg). Finally, animals in the VEH-VEH group (n = 7) received an i.p. injection of

Post-training corticosterone injections enhance response learning in the plus-maze. Results from the water plus-maze task are depicted in Fig. 2. A two-way repeated measures ANCOVA (Group  Day) was computed examining percentage of correct responses on days 2–5 (i.e. Day) and using percentage of correct responses on day 1 (i.e. before drugs were administered) as the covariate. There was a significant main effect of Group (F(2,18) = 3.97, p < .05) and Day (F(3,54) = 12.38, p < .001), but no Group  Day interaction (F(6,54) = 1.60, n.s.). A post-hoc Fisher’s LSD test revealed that animals given post-training 3.0 mg/kg corticosterone displayed enhanced response learning in this task (M = 77.60) relative to animals given vehicle

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Fig. 1. Effect of post-training s.c. injections of corticosterone on memory in the cued water maze task (mean latency in seconds ± standard error of the mean). All animals acquired the task without differences between groups on day 1, i.e. before drugs were administered (Left Panel). Rats given post-training s.c. injection of 3 mg/kg corticosterone displayed enhanced memory on two drug-free probe trials conducted 24 h after training (Right Panel). 1 mg/kg corticosterone did not have a significant effect on memory.

Fig. 2. Effect of post-training s.c. injections of corticosterone on memory for response learning in the water plus-maze task (mean percent correct ± standard error of the mean). Rats receiving post-training administration of 3 mg/kg corticosterone displayed a higher percentage of correct turning responses over training, relative to vehicle-treated control animals. 1 mg/kg corticosterone did not influence memory.

(M = 60.94), p < .05, or animals given a lower 1.0 mg/kg dose of corticosterone (M = 56.55), p < .05. In contrast, there was no difference in memory performance between animals given 1.0 mg/kg corticosterone and animals given vehicle. Taken together, these findings indicate that post-training administration of corticosterone dosedependently facilitated DLS-dependent response learning in the water plus-maze. Experiment 2 Corticosterone-induced enhancement of DLS-dependent response learning is blocked by concurrent administration of propranolol. Results from experiment 2 are depicted in Fig. 3. A three-way repeated measures ANCOVA (Corticosterone  Propranolol  Day) was computed examining percentage of correct responses on days 2–5 (i.e. Day) and using percentage of correct responses on day 1 (i.e. before drugs were administered) as the covariate. There was a significant main effect of Corticosterone (F(1,22) = 9.33, p < .01) and Propranolol (F(1,22) = 6.89, p < .05) and a significant Corticosterone  Propranolol interaction (F(1,22) = 6.39, p < .05). There was a trend toward a significant effect of Day (F(3,66) = 1.81, p = .155),

but no Corticosterone  Propranolol  Day interaction (F(3,66) = .296, n.s.). A post-hoc Fisher’s LSD test revealed that animals in the CORT-VEH group displayed higher percentage of correct responses over the course of training (M = 77.38) relative to animals in the VEH-VEH group (M = 61.31), p < .01. Thus, similar to findings in experiment 1, corticosterone enhanced response learning in the plus-maze task. Fisher’s LSD test also indicated that animals in the PROP-VEH group displayed similar memory performance (M = 57.64) to animals in the VEH-VEH group (M = 61.31, n.s.), suggesting that 3.0 mg/kg propranolol did not by itself influence response learning in this task. Animals given concurrent administration of corticosterone and propranolol (i.e. the PROP-CORT group) also displayed similar memory performance (M = 61.91) to animals in the VEH-VEH group (M = 61.31, n.s.) and animals in the PROP-VEH group (M = 57.64, n.s.). In contrast, there was a significant difference in memory performance between animals in the CORT-VEH group and animals in the PROP-CORT group (M = 61.91, p < .01). Taken together, these results indicate that concurrent propranolol administration at a dose that alone did not influence memory blocked the corticosterone-induced enhancement of response learning.

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Fig. 3. Effect of concurrent i.p. injections of propranolol on the corticosterone-induced enhancement of response learning in the water-plus maze task (mean percent correct ± standard error of the mean). Animals receiving injections of corticosterone (CORT-VEH) displayed enhanced memory, relative to animals receiving vehicle alone (VEH-VEH) or animals receiving concurrent injections of corticosterone and propranolol (CORTPROP). Propranolol by itself (PROP-VEH) did not influence memory. Findings indicate that propranolol at a dose that alone did not influence memory blocked the corticosterone-induced enhancement of memory.

DISCUSSION The present findings indicate that post-training peripheral administration of corticosterone facilitated memory in the DLS-dependent cued water maze and ‘‘response” plusmaze tasks. The use of post-training drug administration potentially prevented corticosterone from influencing online non-mnemonic processes (e.g. perception, motor behavior, etc) that operate during acquisition. Consistent with this suggestion, post-training administration of corticosterone following water maze training does not alter swim speed 24 h later (e.g. Sandi et al., 1997). It is reasonable to hypothesize that post-training corticosterone enhanced DLS-dependent memory in the present study by facilitating memory consolidation. Indeed, glucocorticoid administration 1 h after training (i.e. putatively outside the window of consolidation) does not influence dorsal striatum-dependent memory (Medina et al., 2007). Importantly, the present findings also indicate that the corticosterone-induced enhancement of response learning was blocked by concurrent administration of the b-adrenoreceptor antagonist propranolol. This provides novel evidence suggesting that glucocorticoid enhancement of DLS-dependent memory requires concurrent noradrenergic activity. The findings of experiment 2 are consistent with previous evidence indicating that glucocorticoid and noradrenergic mechanisms interact to influence learning and memory processes. Blockade of noradrenergic activity prevents glucocorticoid administration from enhancing consolidation of hippocampus- and amygdala-dependent cognitive/emotional memory (Quirarte et al., 1997; Roozendaal et al., 2006a,b). In addition, adrenoreceptor antagonists prevent corticosterone from impairing retrieval of cognitive/spatial memory (Roozendaal et al., 2004a,b,c; Schwabe et al., 2009). The present findings indicate that blockade of noradrenergic activity similarly prevents glucocorticoid stimulation from modulating DLS-dependent habit memory.

The effect of corticosterone administration on DLS-dependent memory resembles the memoryenhancing effects of emotional arousal. Administration of anxiogenic drugs or exposure to psychologically or ecologically valid stressors enhances DLS-dependent memory across a wide range of tasks (e.g. Leong and Packard, 2014; for reviews, see Packard and Goodman, 2012; Schwabe, 2013). The memory modulatory properties of emotional arousal on memory may be partially attributed to the release of adrenal stress hormones including glucocorticoids and adrenaline (McGaugh, 2004). Consistent with this suggestion, blockade of mineralocorticoid or b-adrenoreceptor activity is sufficient to prevent the stress-induced enhancement of habit memory (Schwabe et al., 2010a, 2011b). In learning situations where robust emotional arousal is not elicited, simultaneous administration of hydrocortisone and the a2-adrenoreceptor antagonist yohimbine enhances DLS-dependent habit memory, whereas the administration of either drug alone remains ineffective (Schwabe et al., 2010b, 2013). Thus, it is possible that both glucocorticoid and noradrenergic mechanisms need to be active for enhancement of habit memory to occur. Corticosterone administration alone might only enhance habit memory when the learning task elicits emotional arousal and when this emotional arousal leads to a sufficient rise in noradrenergic activity. In an object recognition task, corticosterone administration by itself may only influence recognition memory when the learning situation evokes emotional arousal and a consequent release in brain noradrenaline (Roozendaal et al., 2006b). In the present water maze tasks, mild swimming stress may have been sufficient to increase brain noradrenaline and thus allow corticosterone administration to be effective. However, propranolol administration may have attenuated the rise in noradrenergic activity produced by swimming stress, thus rendering corticosterone administration ineffective. Considering that all drugs were administered peripherally, drug treatments may have influenced learning and memory processes in the present study via

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action on several brain regions. Corticosterone readily crosses the blood–brain barrier and binds to high-affinity mineralocorticoid and low-affinity glucocorticoid receptors in the rat brain (Reul and de Kloet, 1985; de Kloet et al., 1993). The dorsal striatum itself expresses glucocorticoid receptors (Ahima and Harlan, 1990, 1991; Morimoto et al., 1996), yet remains relatively devoid of mineralocorticoid receptors (Agarwal et al., 1993). Therefore, it is possible that in the present study peripheral corticosterone administration enhanced DLS-dependent habit memory directly by activating glucocorticoid receptors in the DLS. Consistent with this hypothesis, direct administration of corticosterone into the dorsal striatum enhances memory consolidation in inhibitory avoidance and cued water maze tasks (Medina et al., 2007; Quirarte et al., 2009; Sa´nchez-Resendis et al., 2012). However, it should be noted that in these previous studies corticosterone infusions were not selective to the medial or lateral aspects of the dorsal striatum, and therefore drug administrations may have influenced memory consolidation by increasing glucocorticoid activity in the dorsomedial striatum (DMS), DLS, or both. However, a subsequent study indicated that when corticosterone was selectively infused into the DMS, memory consolidation in the cued water maze remained unaffected (Lozano et al., 2013). Therefore, corticosterone might influence DLS-dependent memory in the cued water maze directly via glucocorticoid activity in the more lateral aspects of the dorsal striatum. In addition, given that the DLS also contains b-adrenoreceptors (Wanaka et al., 1989; Paschalis et al., 2009), it is possible that propranolol prevented the corticosterone-induced enhancement of habit memory in part by blocking b-adrenoreceptors in the DLS. Another important brain structure implicated in the emotional modulation of memory is the basolateral complex of the amygdala (BLA; McGaugh, 2004; Packard, 2009a,b; Roozendaal et al., 2009). Lesion or inactivation of the BLA blocks enhancement of DLSdependent habit memory produced by the administration of anxiogenic drugs or exposure to psychological or behavioral stressors (Kim et al., 2001; Packard and Gabriele, 2009; Leong and Packard, 2014). In addition, intra-BLA infusion of drugs that boost noradrenergic activity is sufficient to enhance DLS-dependent habit memory (Packard and Wingard, 2004; Elliott and Packard, 2008; Wingard and Packard, 2008), suggesting that the BLA noradrenergic system might have a critical role in the emotional enhancement of habit memory. The BLA has also been verified as an important locus for the effects of glucocorticoid and noradrenergic interactions on memory (Roozendaal et al., 2009). Stimulation of glucocorticoid receptors in the BLA enhances memory in an inhibitory avoidance task, and this effect may be attributed to glucocorticoids’ facilitation of BLA b-adrenoreceptors, which in turn stimulates the cAMPdependent protein kinase pathway (Roozendaal et al., 2002). Thus, the enhancing effect of BLA glucocorticoid receptor stimulation on memory is prevented following blockade of b-adrenoreceptors in the BLA (Quirarte et al., 1997). A similar mechanism centered on the BLA might underlie propranolol’s ability to block the

corticosterone-induced enhancement of DLS-dependent habit memory observed in the present study. Another brain region implicated in the stress/anxietyinduced enhancement of DLS-dependent memory is the hippocampus. In some learning situations, lesion or inactivation of the hippocampal formation is associated with enhanced DLS-dependent memory processes (Packard et al., 1989; McDonald and White, 1993; Schroeder et al., 2002). Likewise, stress/anxiety-induced impairment of hippocampal memory function may be associated with enhancement of DLS-dependent response learning in the water maze (Kim et al., 2001; Wingard and Packard, 2008; Packard and Gabriele, 2009). Given that systemic or intra-hippocampal glucocorticoids might similarly produce impairments in hippocampus-dependent memory retrieval (e.g. Luine et al., 1993; de Quervain et al., 1998; Roozendaal et al., 2003), corticosterone might have enhanced DLSdependent memory in the present study indirectly via disruption of the hippocampus-dependent memory system. Moreover, considering that propranolol administration can prevent glucocorticoids from impairing hippocampus-dependent memory retrieval (Roozendaal et al., 2004a; de Quervain et al., 2007), it is possible that propranolol’s ability to block the corticosterone-induced enhancement of habit memory might also have occurred indirectly via propranolol-mediated rescue of hippocampal function. However, in contrast to pre-retrieval administration, post-training glucocorticoid administration is associated with enhancement of hippocampus-dependent memory (Quirarte et al., 1997). Considering that the present study also utilized post-training drug administrations, it is reasonable to hypothesize that the effects of glucocorticoids on DLS-dependent memory may not be readily attributed to hippocampal dysfunction, but rather by glucocorticoid activity within the BLA and/or the DLS. Future studies employing direct intra-cerebral drug injections will be necessary to examine these hypotheses. The present finding that propranolol blocked the corticosterone-induced enhancement of DLS-dependent habit memory may provide novel clinical insights into the neurobiological mechanisms and potential treatments for some human psychopathologies. Multiple investigators have suggested that the formation and expression of habit-like symptoms might reflect dysfunction of the dorsal striatum-dependent memory system in a variety of neuropsychiatric disorders, including Tourette syndrome, obsessive-compulsive disorder, posttraumatic stress disorder, drug addiction and relapse, and others (White, 1996; Everitt and Robbins, 2005; Schwabe et al., 2011; Goodman et al., 2012, 2014; Berner and Marsh, 2014; Gillan and Robbins, 2014). Moreover, consistent with the emotional enhancement of habit memory, stress/anxiety may sometimes constitute a co-factor that contributes to the formation or exacerbation of habit-like symptoms in these disorders. Glucocorticoid release is a natural part of the stress response that, as suggested by the present findings, may enhance DLS-dependent habit memory. If this glucocorticoid-mediated process is part of the mechanism that allows stress to influence habit-like symptoms, then it

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would be reasonable to hypothesize that the administration of propranolol might be useful in combating the stress-induced exacerbation of habitual behaviors in human psychopathology.

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(Accepted 8 October 2015) (Available online xxxx)