Publications by authors named "Stan B Floresco"

111 Publications

Prefrontal-hippocampal interactions supporting the extinction of emotional memories: the retrieval stopping model.

Neuropsychopharmacology 2021 Aug 26. Epub 2021 Aug 26.

Department of Psychology, and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, Canada.

Neuroimaging has revealed robust interactions between the prefrontal cortex and the hippocampus when people stop memory retrieval. Efforts to stop retrieval can arise when people encounter reminders to unpleasant thoughts they prefer not to think about. Retrieval stopping suppresses hippocampal and amygdala activity, especially when cues elicit aversive memory intrusions, via a broad inhibitory control capacity enabling prepotent response suppression. Repeated retrieval stopping reduces intrusions of unpleasant memories and diminishes their affective tone, outcomes resembling those achieved by the extinction of conditioned emotional responses. Despite this resemblance, the role of inhibitory fronto-hippocampal interactions and retrieval stopping broadly in extinction has received little attention. Here we integrate human and animal research on extinction and retrieval stopping. We argue that reconceptualising extinction to integrate mnemonic inhibitory control with learning would yield a greater understanding of extinction's relevance to mental health. We hypothesize that fear extinction spontaneously engages retrieval stopping across species, and that controlled suppression of hippocampal and amygdala activity by the prefrontal cortex reduces fearful thoughts. Moreover, we argue that retrieval stopping recruits extinction circuitry to achieve affect regulation, linking extinction to how humans cope with intrusive thoughts. We discuss novel hypotheses derived from this theoretical synthesis.
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http://dx.doi.org/10.1038/s41386-021-01131-1DOI Listing
August 2021

Cannabinoid receptor type 1 antagonists alter aspects of risk/reward decision making independent of toluene-mediated effects.

Psychopharmacology (Berl) 2021 Jul 22. Epub 2021 Jul 22.

Department of Neuroscience, Medical University of South Carolina, MSC 861, 30 Courtenay Drive, Charleston, SC, 29425-5712, USA.

Drugs of abuse including cannabis and inhalants impair risk/reward decision making. Cannabis use is often concurrent with inhalant intoxication; yet, preclinical studies investigating the role of endocannabinoids in inhalant misuse are limited. To address this gap in the literature, we used the well-validated probabilistic discounting task to assess risk/reward decision making in rodents following combinations of toluene vapor (a common inhalant) and manipulations of cannabinoid receptor type 1 (CB1R) signaling. As reported previously, acute exposure to toluene vapor disrupted behavioral flexibility during probabilistic discounting. Systemic administration of the CB1R inverse agonist AM281 did not prevent toluene-induced alterations in risky choices, but did independently reduce win-stay behavior, increase choice latency, and increase omissions. Toluene-induced deficits in probabilistic discounting are thought to involve impaired medial prefrontal cortex (mPFC) activity. As we previously reported that some of toluene's inhibitory effects on glutamatergic signaling in the mPFC are endocannabinoid-dependent, we tested the hypothesis that mPFC CB1R activity mediates toluene-induced deficits in discounting. However, bilateral injection of the CB1R inverse agonist AM251 prior to toluene vapor exposure had no effect on toluene-induced changes in risk behavior. In a final set of experiments, we injected the CB1R inverse agonist AM251 (5 and 50 ng), the CB1R agonist WIN55,212-2 (50 ng and 500 ng), or vehicle into the mPFC prior to testing. While mPFC CB1R stimulation did not affect any of the measures tested, the CB1R inverse agonist caused a dose-dependent reduction in win-stay behavior without altering any other measures. Together, these studies indicate that toluene-induced deficits in probabilistic discounting are largely distinct from CB1R-dependent effects that include decreased effectiveness of positive reinforcement (mPFC CB1Rs), decision making speed, and task engagement (non-mPFC CB1Rs).
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http://dx.doi.org/10.1007/s00213-021-05914-8DOI Listing
July 2021

Hippocampal neurogenesis promotes preference for future rewards.

Mol Psychiatry 2021 May 21. Epub 2021 May 21.

Department of Psychology, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada.

Adult hippocampal neurogenesis has been implicated in a number of disorders where reward processing is disrupted but whether new neurons regulate specific aspects of reward-related decision making remains unclear. Given the role of the hippocampus in future-oriented cognition, here we tested whether adult neurogenesis regulates preference for future, advantageous rewards in a delay discounting paradigm for rats. Indeed, blocking neurogenesis caused a profound aversion for delayed rewards, and biased choice behavior toward immediately available, but smaller, rewards. Consistent with a role for the ventral hippocampus in impulsive decision making and future-thinking, neurogenesis-deficient animals displayed reduced activity in the ventral hippocampus. In intact animals, delay-based decision making restructured dendrites and spines in adult-born neurons and specifically activated adult-born neurons in the ventral dentate gyrus, relative to dorsal activation in rats that chose between immediately-available rewards. Putative developmentally-born cells, located in the superficial granule cell layer, did not display task-specific activity. These findings identify a novel and specific role for neurogenesis in decisions about future rewards, thereby implicating newborn neurons in disorders where short-sighted gains are preferred at the expense of long-term health.
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http://dx.doi.org/10.1038/s41380-021-01165-3DOI Listing
May 2021

Ventral Pallidum GABA Neurons Mediate Motivation Underlying Risky Choice.

J Neurosci 2021 May 9;41(20):4500-4513. Epub 2021 Apr 9.

Department of Neurobiology & Behavior, University of California, Irvine, California 92697.

Pursuing rewards while avoiding danger is an essential function of any nervous system. Here, we examine a new mechanism helping rats negotiate the balance between risk and reward when making high-stakes decisions. Specifically, we focus on GABA neurons within an emerging mesolimbic circuit nexus: the ventral pallidum (VP). These neurons play a distinct role from other VP neurons in simple motivated behaviors in mice, but their role in more complex motivated behaviors is unknown. Here, we interrogate the behavioral functions of VP neurons in male and female transgenic GAD1:Cre rats (and WT littermates), using a reversible chemogenetic inhibition approach. Using a behavioral assay of risky decision-making, and of the food-seeking and shock-avoidance components of this task, we show that engaging inhibitory G signaling specifically in VP neurons suppresses motivation to pursue highly salient palatable foods, and possibly also motivation to avoid being shocked. In contrast, inhibiting these neurons did not affect seeking of low-value food, free consumption of palatable food, or unconditioned affective responses to shock. Accordingly, when rats considered whether to pursue food despite potential for shock in a risky decision-making task, inhibiting VP neurons caused them to more readily select a small but safe reward over a large but dangerous one, an effect not seen in the absence of shock threat. Together, results indicate that VP neurons are critical for high-stakes adaptive responding that is necessary for survival, but which may also malfunction in psychiatric disorders. In a dynamic world, it is essential to implement appropriate behaviors under circumstances involving rewards, threats, or both. Here, we demonstrate a crucial role for VP neurons in high-stakes motivated behavior of several types. We show that this VP role in motivation impacts decision-making, as inhibiting these neurons yields a conservative, risk-averse strategy not seen when the task is performed without threat of shock. These new roles for VP neurons in behavior may inform future strategies for treating addiction, and other disorders of maladaptive decision-making.
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http://dx.doi.org/10.1523/JNEUROSCI.2039-20.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8152612PMC
May 2021

Early life adversity promotes resilience to opioid addiction-related phenotypes in male rats and sex-specific transcriptional changes.

Proc Natl Acad Sci U S A 2021 02;118(8)

Department of Psychology and Neuroscience Program, Temple University, Philadelphia, PA 19122;

Experiencing some early life adversity can have an "inoculating" effect that promotes resilience in adulthood. However, the mechanisms underlying stress inoculation are unknown, and animal models are lacking. Here we used the limited bedding and nesting (LBN) model of adversity to evaluate stress inoculation of addiction-related phenotypes. In LBN, pups from postnatal days 2 to 9 and their dams were exposed to a low-resource environment. In adulthood, they were tested for addiction-like phenotypes and compared to rats raised in standard housing conditions. High levels of impulsivity are associated with substance abuse, but in males, LBN reduced impulsive choice compared to controls. LBN males also self-administered less morphine and had a lower breakpoint on a progressive ratio reinforcement schedule than controls. These effects of LBN on addiction-related behaviors were not found in females. Because the nucleus accumbens (NAc) mediates these behaviors, we tested whether LBN altered NAc physiology in drug-naïve and morphine-exposed rats. LBN reduced the frequency of spontaneous excitatory postsynaptic currents in males, but a similar effect was not observed in females. Only in males did LBN prevent a morphine-induced increase in the AMPA/NMDA ratio. RNA sequencing was performed to delineate the molecular signature in the NAc associated with LBN-derived phenotypes. LBN produced sex-specific changes in transcription, including in genes related to glutamate transmission. Collectively, these studies reveal that LBN causes a male-specific stress inoculation effect against addiction-related phenotypes. Identifying factors that promote resilience to addiction may reveal novel treatment options for patients.
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http://dx.doi.org/10.1073/pnas.2020173118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923376PMC
February 2021

Learning is a matter of history and relevance for lateral hypothalamus.

Authors:
Stan B Floresco

Nat Neurosci 2021 03;24(3):295-296

Department of Psychology and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada.

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http://dx.doi.org/10.1038/s41593-020-00781-6DOI Listing
March 2021

Medial orbitofrontal cortex dopamine D/D receptors differentially modulate distinct forms of probabilistic decision-making.

Neuropsychopharmacology 2021 06 15;46(7):1240-1251. Epub 2021 Jan 15.

Department of Psychology, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada.

Efficient decision-making involves weighing the costs and benefits associated with different actions and outcomes to maximize long-term utility. The medial orbitofrontal cortex (mOFC) has been implicated in guiding choice in situations involving reward uncertainty, as inactivation in rats alters choice involving probabilistic rewards. The mOFC receives considerable dopaminergic input, yet how dopamine (DA) modulates mOFC function has been virtually unexplored. Here, we assessed how mOFC D and D receptors modulate two forms of reward seeking mediated by this region, probabilistic reversal learning and probabilistic discounting. Separate groups of well-trained rats received intra-mOFC microinfusions of selective D or D antagonists or agonists prior to task performance. mOFC D and D blockade had opposing effects on performance during probabilistic reversal learning and probabilistic discounting. D blockade impaired, while D blockade increased the number of reversals completed, both mediated by changes in errors and negative feedback sensitivity apparent during the initial discrimination of the task, which suggests changes in probabilistic reinforcement learning rather than flexibility. Similarly, D blockade reduced, while D blockade increased preference for larger/risky rewards. Excess D stimulation had no effect on either task, while excessive D stimulation impaired probabilistic reversal performance, and reduced both profitable risky choice and overall task engagement. These findings highlight a previously uncharacterized role for mOFC DA, showing that D and D receptors play dissociable and opposing roles in different forms of reward-related action selection. Elucidating how DA biases behavior in these situations will expand our understanding of the mechanisms regulating optimal and aberrant decision-making.
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http://dx.doi.org/10.1038/s41386-020-00931-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134636PMC
June 2021

Differential effects of d- and l-enantiomers of govadine on distinct forms of cognitive flexibility and a comparison with dopaminergic drugs.

Psychopharmacology (Berl) 2021 Apr 11;238(4):1069-1085. Epub 2021 Jan 11.

Departments of Psychology, Psychiatry and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2136 West Mall, Vancouver, BC, V6T 1Z4, Canada.

Rationale: There is an urgent need for novel drugs for treating cognitive deficits that are defining features of schizophrenia. The individual d- and l-enantiomers of the tetrahydroprotoberberine (THPB) d,l-govadine have been proposed for the treatment of cognitive deficiencies and positive symptoms of schizophrenia, respectively.

Objectives: We examined the effects of d-, l-, or d,l-govadine on two distinct forms of cognitive flexibility perturbed in schizophrenia and compared them to those induced by a selective D1 receptor agonist and D2 receptor antagonist.

Methods: Male rats received d-, l-, or d,l-govadine (0.3, 0.5, and 1.0 mg/kg), D1 agonist SKF81297(0.1, 0.3, and 1.0 mg/kg), or D2 antagonist haloperidol (0.1-0.2 mg/kg). Experiment 1 used a strategy set-shifting task (between-subjects). In experiment 2, well-trained rats were tested on a probabilistic reversal task (within-subjects).

Results: d-Govadine improved set-shifting across all doses, whereas higher doses of l-govadine impaired set-shifting. SKF81297 reduced perseverative errors at the lowest dose. Low/high doses of haloperidol increased/decreased set-shifting errors, the latter "improvement" attributable to impaired retrieval of a previous acquired rule. Probabilistic reversal performance was less affected by these drugs, but d-govadine reduced errors during the first reversal, whereas l-govadine impaired initial discrimination learning. d,l-Govadine had no reliable cognitive effects but caused psychomotor slowing like l-govadine and haloperidol.

Conclusions: These findings further highlight differences between two enantiomers of d,l-govadine that may reflect differential modulation of D1 and D2 receptors. These preclinical findings give further impetus to formal clinical evaluation of d-govadine as a treatment for cognitive deficiencies related to schizophrenia.
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http://dx.doi.org/10.1007/s00213-020-05754-yDOI Listing
April 2021

LTD is involved in the formation and maintenance of rat hippocampal CA1 place-cell fields.

Nat Commun 2021 01 4;12(1):100. Epub 2021 Jan 4.

Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, V6T 1Z7, BC, Canada.

Hippocampal synaptic plasticity includes both long-term potentiation (LTP) and long-term depression (LTD) of synaptic strength, and has been implicated in shaping place field representations that form upon initial exposure to a novel environment. However, direct evidence causally linking either LTP or LTD to place fields remains limited. Here, we show that hippocampal LTD regulates the acute formation and maintenance of place fields using electrophysiology and blocking specifically LTD in freely-moving rats. We also show that exploration of a novel environment produces a widespread and pathway specific de novo synaptic depression in the dorsal hippocampus. Furthermore, disruption of this pathway-specific synaptic depression alters both the dynamics of place field formation and the stability of the newly formed place fields, affecting spatial memory in rats. These results suggest that activity-dependent synaptic depression is required for the acquisition and maintenance of novel spatial information.
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http://dx.doi.org/10.1038/s41467-020-20317-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782827PMC
January 2021

Dorsomedial striatal contributions to different forms of risk/reward decision making.

Neurobiol Learn Mem 2021 02 28;178:107369. Epub 2020 Dec 28.

Department of Psychology and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2136 West Mall, Vancouver, BC V6T 1Z4, Canada. Electronic address:

Optimal decision making involving reward uncertainty is integral to adaptive goal-directed behavior. In some instances, these decisions are guided by internal representations of reward history, whereas in other situations, external cues inform a decision maker about how likely certain actions are to yield reward. Different regions of the frontal lobe form distributed networks with striatal and amygdalar regions that facilitate different types of risk/reward decision making. The dorsal medial striatum (DMS) is one key output region of the prefrontal cortex, yet there have been few preclinical studies investigating the involvement of the DMS in different forms of risk/reward decision making. The present study addressed this issue, wherein separate groups of male rats were trained on one of two tasks where they chose between a small/certain or a large/risky reward. In a probabilistic discounting task, reward probabilities changed systematically over blocks of trials (100-6.25% or 6.25-100%), requiring rats to use internal representations of reward history to guide choice. Cue-guided decision-making was assessed with a "Blackjack" task, where different auditory cues indicated the odds associated with the large/risky option (50 or 12.5%). Inactivation of the DMS with GABA agonists impaired adjustments in choice biases during probabilistic discounting, resulting in either increases or decreases in risky choice as the probabilities associated with the large/risky reward decreased or increased over a session. In comparison, DMS inactivation increased risky choices on poor-odds trials on the Blackjack task, which was associated with a reduced impact that non-rewarded choices had on subsequent choices. DMS inactivation also impaired performance of an auditory conditional discrimination. These findings highlight a previously uncharacterized role for the DMS in facilitating flexible action selection during multiple forms of risk/reward decision making.
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http://dx.doi.org/10.1016/j.nlm.2020.107369DOI Listing
February 2021

Central CRF and acute stress differentially modulate probabilistic reversal learning in male and female rats.

Behav Brain Res 2021 01 28;397:112929. Epub 2020 Sep 28.

Department of Psychology and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2136 West Mall, Vancouver, BC, V6T 1Z4, Canada. Electronic address:

Acute stress can have variable and sometimes sex-dependent effects on different executive functions, including cognitive flexibility, some of which may be mediated by increased corticotropin releasing factor (CRF). Previous studies on the effects of stress and CRF on cognitive flexibility have used procedures entailing deterministic rewards, yet how they may alter behavior when outcomes are probabilistic is unclear. The present study examined how acute stress and increased CRF activity alters probabilistic reversal learning (PRL) in male and female rats. Rats learned to discriminate between a 'correct' lever rewarded on 80 % of trials, and an "incorrect" lever delivering reward on 20 % of trials, with reward contingencies reversed after 8 consecutive correct choices. Separate groups received either intracerebroventricular infusions of CRF (3 μg) or restraint stress prior to a PRL session. Experiments examined how these manipulations affected learning when given prior to a one-day acquisition test or during performance in well-trained rats. Exogenous CRF, and to a lesser extent acute stress, impaired motivation across sexes, slowing deliberation times and increasing the number of trials omitted, particularly following a switch in reward contingencies. Neither manipulation significantly altered errors or reversal performance. However, increased CRF activity reduced negative feedback sensitivity. Across manipulations, females showed increased omissions and choice latencies, and were less sensitive to feedback than males. These results reveal the complexity with which stress, CRF, sex, and experience interact to alter aspects of motivation and probabilistic reinforcement learning and provide insight into how CRF activity may contribute to symptoms of stress-related disorders.
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http://dx.doi.org/10.1016/j.bbr.2020.112929DOI Listing
January 2021

Prefrontal cortical and nucleus accumbens contributions to discriminative conditioned suppression of reward-seeking.

Learn Mem 2020 10 15;27(10):429-440. Epub 2020 Sep 15.

Department of Psychology and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.

Fear can potently inhibit ongoing behavior, including reward-seeking, yet the neural circuits that underlie such suppression remain to be clarified. Prior studies have demonstrated that distinct subregions of the rodent medial prefrontal cortex (mPFC) differentially affect fear behavior, whereby fear expression is promoted by the more dorsal prelimbic cortex (PL) and inhibited by the more ventral infralimbic cortex (IL). These mPFC regions project to subregions of the nucleus accumbens, the core (NAcC) and shell (NAcS), that differentially contribute to reward-seeking as well as affective processes that may be relevant to fear expression. Here, we investigated how these mPFC and NAc subregions contribute to discriminative fear conditioning, assessed by conditioned suppression of reward-seeking. Bilateral inactivation of the NAcS or PL reduced the expression of conditioned suppression to a shock-associated CS+, whereas NAcC inactivation reduced reward-seeking without affecting suppression. IL inactivation caused a general reduction in conditioned suppression following discriminative conditioning, but not when using a single-stimulus design. Pharmacological disconnection of the PL → NAcS pathway revealed that this projection mediates conditioned suppression. These data add to a growing literature implicating discrete cortico-striatal pathways in the suppression of reward-seeking in response to aversive stimuli. Dysfunction within related structures may contribute to aberrant patterns of behavior in psychiatric illnesses including substance use disorders.
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http://dx.doi.org/10.1101/lm.051912.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497111PMC
October 2020

Risk-based decision making in rats: Modulation by sex and amphetamine.

Horm Behav 2020 09 18;125:104815. Epub 2020 Jul 18.

Department of Psychology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; Graduate Program in Neuroscience, University of British Columbia, Vancouver, BC V6T 1Z3, Canada. Electronic address:

Decision-making is a complex process essential to daily adaptation in many species. Risk is an inherent aspect of decision-making and it is influenced by gonadal hormones. Testosterone and 17β-estradiol may modulate decision making and impact the mesocorticolimbic dopamine pathway. Here, we explored sex differences, the effect of gonadal hormones and the dopamine agonist amphetamine on risk-based decision making. Intact or gonadectomised (GDX) male and female rats underwent to a probabilistic discounting task. High and low doses of testosterone propionate (1.0 or 0.2 mg) and 17β-estradiol benzoate (0.3 μg) were administered to assess acute effects on risk-based decision making. After 3-days of washout period, intact and GDX rats received high or low (0.5 or 0.125 mg/kg) doses of amphetamine and re-tested in the probabilistic discounting task. Under baseline conditions, males made more risky choices during probability discounting compared to female rats, particularly in the lower probability blocks, but GDX did not influence risky choice. The high, but not the low dose, of testosterone modestly reduced risky decision making in GDX male rats. Conversely, 17β-estradiol had no significant effect on risky choice regardless of GDX status in either sex. Lastly, a higher dose of amphetamine increased risky decision making in both intact males and females, but had no effect in GDX rats. These findings demonstrated sex differences in risk-based decision making, with males showing a stronger bias toward larger, uncertain rewards. GDX status influenced the effects of amphetamine, suggesting different dopaminergic regulation in risk-based choices among males and females.
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http://dx.doi.org/10.1016/j.yhbeh.2020.104815DOI Listing
September 2020

Prelimbic and Infralimbic Prefrontal Regulation of Active and Inhibitory Avoidance and Reward-Seeking.

J Neurosci 2020 06 11;40(24):4773-4787. Epub 2020 May 11.

Department of Psychology and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, B.C., Canada V6T 1Z3

Flexible initiation or suppression of actions to avoid aversive events is crucial for survival. The prelimbic (PL) and infralimbic (IL) regions of the medial prefrontal cortex (mPFC) have been implicated in different aspects of avoidance and reward-seeking, but their respective contribution in instigating versus suppressing actions in aversive contexts remains to be clarified. We examined mPFC involvement in different forms of avoidance in rats well trained on different cued lever-press avoidance tasks. Active/inhibitory avoidance required flexible discrimination between auditory cues signaling foot-shock could be avoided by making or withholding instrumental responses. On a simpler active avoidance task, a single cue signaled when a lever press would avoid shock. PL inactivation disrupted active but not inhibitory avoidance on the discriminative task while having no effect on single-cued avoidance. In comparison, IL inactivation broadly impaired active and inhibitory avoidance. Conversely, on a cued appetitive go/no-go task, both IL and PL inactivation impaired inhibitory but not active reward-seeking, the latter effect being diametrically opposite to that observed on the avoidance task. These findings highlight the complex manner in which different mPFC regions aid in initiating or inhibiting actions in the service of avoiding aversive outcomes or obtaining rewarding ones. IL facilitates active avoidance but suppress inappropriate actions in appetitive and aversive contexts. In contrast, contextual valence plays a critical role in how the PL is recruited in initiating or suppressing actions, which may relate to the degree of cognitive control required to flexibly negotiate response or motivational conflicts and override prepotent behaviors. Choosing to make or withhold actions in a context-appropriate manner to avoid aversive events or obtain other goals is a critical survival skill. Different medial prefrontal cortex (mPFC) regions have been implicated in certain aspects of avoidance, but their contributions to instigating or suppressing actions remains to be clarified. Here, we show that the dorsal, prelimbic (PL) region of the medial PFC aids active avoidance in situations requiring flexible mitigation of response conflicts, but also aids in withholding responses to obtain rewards. In comparison the ventral infralimbic (IL) cortex plays a broader role in active and inhibitory avoidance as well as suppressing actions to obtain rewards. These findings provide insight into mechanisms underlying normal and maladaptive avoidance behaviors and response inhibition.
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http://dx.doi.org/10.1523/JNEUROSCI.0414-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294792PMC
June 2020

A role for neurogenesis in probabilistic reward learning.

Behav Neurosci 2020 Aug 7;134(4):283-295. Epub 2020 May 7.

Department of Psychology.

Rewards are often unreliable and optimal choice requires behavioral flexibility and learning about the probabilistic nature of uncertain rewards. Probabilistic learning occurs over multiple trials, often without conscious knowledge, and is traditionally associated with striatal function. While the hippocampus is classically recognized for its role in memory for individual experiences, recent work indicates that it is also involved in probabilistic forms of learning but little is known about the features that support such learning. We hypothesized that adult neurogenesis may be involved, because adult-born neurons contribute to both learning and reward-related behaviors. To test this, we used an appetitive probabilistic reversal learning task where a correct lever is rewarded with 80% probability and an incorrect lever is rewarded with 20% probability. Behavioral flexibility was assessed by switching correct-incorrect lever identities after 8 consecutive correct choices. Transgenic male rats that lacked adult neurogenesis displayed an initial deficit in discriminating the correct and incorrect levers, but they were not impaired at reversing behavior when the reward contingencies switched. When reward was withheld after a correct lever choice, neurogenesis-deficient rats were more likely to choose the incorrect lever on the subsequent trial. Also, rats with intact neurogenesis were more sensitive to reward at the incorrect lever. Differences were not observed in control transgenic rats that had intact neurogenesis. These results identify a novel role for neurogenesis in learning about uncertain, probabilistic rewards. Altered sensitivity to reward and negative feedback furthermore implicates neurogenesis in cognitive phenotypes associated with mood disorders such as depression. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
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http://dx.doi.org/10.1037/bne0000370DOI Listing
August 2020

Differential effects of corticotropin-releasing factor and acute stress on different forms of risk/reward decision-making.

Neurobiol Learn Mem 2020 03 17;169:107167. Epub 2020 Jan 17.

Department of Psychology and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2136 West Mall, Vancouver, BC V6T 1Z4, Canada. Electronic address:

Acute stress and corticotropin-releasing factor (CRF) have been show to perturb cost/benefit decision making involving effort costs. However, previous studies on how stress manipulations affect decisions involving reward uncertainty have yielded variable results. To provide additional insight into this issue, the current study investigated how central CRF infusion and acute restraint stress alter different forms of risk/reward decision-making guided by internal representations of risk/reward contingencies or external informative cues. Male rats were well-trained on one of two tasks that required choice between a small/certain or a large/risky reward. On a probabilistic discounting task, the probability of obtaining the larger reward increased or decreased systematically over blocks of trials (100-6.25%). On a cue-guided Blackjack task, reward probabilities (50% or 12.5%) were signaled by discriminative auditory cues. CRF (1 or 3 μg) was infused intracerebroventricularly (ICV) or one-hour of restraint stress was administered prior to behavioral testing. Neither CRF nor acute stress altered risky choice on probabilistic discounting, but did increase trial omissions in the latter part of the session. Conversely on the Blackjack task, CRF reduced risky choice on good-odds trials (50%), whereas acute stress increased reward sensitivity. CRF but not acute stress also slowed decision latencies across tasks. These data reveal complex and differential manners in which increased CRF activity and acute stress alter distinct forms of risk/reward decision-making, particularly those guided by external cues.
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http://dx.doi.org/10.1016/j.nlm.2020.107167DOI Listing
March 2020

Effects of aging on testosterone and androgen receptors in the mesocorticolimbic system of male rats.

Horm Behav 2020 04 31;120:104689. Epub 2020 Jan 31.

Department of Psychology and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada; Department of Zoology, University of British Columbia, Vancouver, BC, Canada. Electronic address:

As males age, systemic testosterone (T) levels decline. T regulates executive function, a collection of cognitive processes that are mediated by the mesocorticolimbic system. Here, we examined young adult (5 months) and aged (22 months) male Fischer 344 × Brown Norway rats, and measured systemic T levels in serum and local T levels in microdissected nodes of the mesocorticolimbic system (ventral tegmental area (VTA), nucleus accumbens (NAc), medial prefrontal cortex (mPFC), and orbitofrontal cortex (OFC)). We also measured androgen receptor (AR) immunoreactivity (-ir) in the mesocorticolimbic system. As expected, systemic T levels decreased with age. Local T levels in mesocorticolimbic regions - except the VTA - also decreased with age. Mesocorticolimbic T levels were higher than serum T levels at both ages. AR-ir was present in the VTA, NAc, mPFC, and OFC and decreased with age in the mPFC. Taken together with previous results, the data suggest that changes in androgen signaling may contribute to changes in executive function during aging.
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http://dx.doi.org/10.1016/j.yhbeh.2020.104689DOI Listing
April 2020

Basolateral amygdala - nucleus accumbens circuitry regulates optimal cue-guided risk/reward decision making.

Prog Neuropsychopharmacol Biol Psychiatry 2020 03 4;98:109830. Epub 2019 Dec 4.

Department of Psychology, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, V6T 1Z3, Canada. Electronic address:

Maladaptive decision making is a characteristic feature of substance use disorder and pathological gambling. Studies in humans and animals have implicated neural circuits that include the basolateral amygdala (BLA) and nucleus accumbens (NAc) in facilitating risk/reward decision making. However, the preclinical literature has focussed primarily on situations where animals use internally-generated information to adapt to changes in reward likelihood, whereas many real-life situations require the use of external stimuli to facilitate context-appropriate behavior. We recently developed the "Blackjack" task, to measure cued risk/reward decision making requiring rats to chose between Small/Certain and Large/Risky rewards, with auditory cues at the start of each trial explicitly informing that the probability of obtaining a large reward was either good (50%) or poor (12.5%). Here we investigated the contribution of the BLA and its interaction with the NAc in guiding these types of decisions. In well-trained male rats, bilateral inactivation of the BLA induced suboptimal decision making, primarily by reducing risky choice on good-odds trials. In comparison, pharmacological disconnection of the BLA and NAc-shell also induced suboptimal decision making, diverting choice from more preferred option by reducing or increasing risky choice on good vs. poor odds trials respectively. Together, these results suggest that the BLA-NAc circuitry plays a crucial role in integrating information provided by discriminative stimuli. Furthermore, this circuitry may aid in guiding action selection of advantageous options in situations to maximize rewards. Finally, they suggest that perturbations in optimal decision making observed in substance abuse and gambling disorders may be driven in part by dysfunction within this circuitry.
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http://dx.doi.org/10.1016/j.pnpbp.2019.109830DOI Listing
March 2020

Amelioration of cognitive impairments induced by GABA hypofunction in the male rat prefrontal cortex by direct and indirect dopamine D agonists SKF-81297 and d-Govadine.

Neuropharmacology 2020 01 6;162:107844. Epub 2019 Nov 6.

Department of Psychology and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, B.C, V6T 2B5, Canada. Electronic address:

Deficits in prefrontal cortex (PFC) GABAergic neurotransmission are linked to cognitive impairments seen in schizophrenia and other disorders, and pharmacological reduction of PFC GABA transmission disrupts processes including working and spatial memory. This provides an opportunity to examine whether compounds capable of neutralizing GABAergic dysfunction may ameliorate these cognitive deficits. PFC dopamine (DA) D receptor activation enhances GABA transmission, raising the possibly that direct or indirect agonists of DA D receptors would be effective in reversing working memory and other forms of cognitive deficits. To test this, male rats were pre-treated with two drugs that augment PFC D signalling before PFC infusion of the GABA antagonist, bicuculline (50 ng) and assessment of spatial working and reference memory function. A moderate dose of the full D agonist SKF-81297 (0.1 mg/kg) completely reversed PFC GABA hypofunction-induced working memory deficits assessed in an delayed-response task, whereas lower and higher doses (0.05 and 0.3 mg/kg respectively) were associated with mild improvements or deleterious effects. Treatment with the tetrahydroprotoberberine d-govadine (0.5 or 1.0 mg/kg), a synthetic compound known to enhance DA release selectively in the PFC, also significantly improved delayed-response working memory function induced by PFC GABA antagonism. Furthermore, administration of the optimal dose of both drugs led to a partial rescue of PFC GABA hypofunction-induced reference and short-term spatial memory impairments assessed on a radial maze task. These findings suggest that modulation of PFC DA signalling via actions on the DA D receptor represents a promising therapeutic strategy for working memory and other cognitive impairments observed in psychiatric disorders, including those with causes that extend beyond DA dysfunction.
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http://dx.doi.org/10.1016/j.neuropharm.2019.107844DOI Listing
January 2020

Dissociable roles for the ventral and dorsal medial prefrontal cortex in cue-guided risk/reward decision making.

Neuropsychopharmacology 2020 03 25;45(4):683-693. Epub 2019 Oct 25.

Department of Psychology and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, V6T 1Z3, Canada.

Converging evidence from studies with animals and humans have implicated separate regions of the medial prefrontal cortex (mPFC) corresponding to the anterior cingulate cortex (ACC), in mediating different aspects of reward-related decisions involving uncertainty or risk. However, the dissociable contributions of subregions of the ACC remain unclear, as discrepancies exist between human neuroimaging findings and preclinical rodent studies. To clarify how ventral vs. dorsal regions of the mPFC contribute to risk/reward decision making, the present study assessed the effects of inactivation of different subregions on performance of a "Blackjack task" that measured cue-guided decision making and shares similarities with paradigms used with humans. Male, Long-Evans rats were well-trained to choose between a Small/Certain reward vs a Large/Risky reward delivered with variable probabilities (i.e., good vs. poor-odds, 50% vs. 12.5%). The odds of obtaining the larger reward was signaled by auditory cues at the start of each trial. Inactivation of the ventral, infralimbic region of the mPFC increased risky choice selectively when the odds of winning were poor. By contrast, inactivation of the prelimbic and anterior cingulate regions of the dorsal mPFC led to suboptimal reductions in risky choice on good-odds trials. The effects of prelimbic vs anterior cingulate inactivations were associated with context-dependent alterations in reward vs negative feedback, respectively. These results further clarify the distinct yet complementary manners in which separate ACC regions promote optimal risk/reward decision making and complement neuroimaging findings that activity in human ventral vs dorsal ACC promotes risk aversion or risky choices.
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http://dx.doi.org/10.1038/s41386-019-0557-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7021677PMC
March 2020

The Abused Inhalant Toluene Impairs Medial Prefrontal Cortex Activity and Risk/Reward Decision-Making during a Probabilistic Discounting Task.

J Neurosci 2019 11 23;39(46):9207-9220. Epub 2019 Sep 23.

Department of Neuroscience,

Inhalant (e.g., toluene) misuse is linked to behavioral and cognitive deficits in humans, yet preclinical studies of the effect of inhalants on higher-order cognition are limited. We addressed this gap in the literature by examining the effect of toluene vapor exposure on risk/reward decision-making in male and female Sprague-Dawley rats using a probabilistic discounting task. In this task, rodents chose a risky/large reward or a safe/small reward, with the odds of risky reinforcement descending or ascending throughout the test session. We observed a dose-dependent, sex-independent deficit in behavioral flexibility during probabilistic discounting caused by acute toluene exposure. Rats exposed to toluene vapor during adolescence and tested as adults performed comparably to air-treated controls and were susceptible to the effects of an acute toluene challenge. These behavioral flexibility deficits observed suggests dysfunctional medial prefrontal cortex (mPFC) activity. To address this hypothesis, we virally expressed the genetically encoded calcium sensor GCaMP6f in glutamatergic mPFC neurons and monitored calcium transients in real-time using fiber photometry. mPFC activity peaked before either lever press during free-choice trials in toluene- and air-treated animals. During forced-choice trials, GCaMP6f transients shifted from pre-risky to pre-safe choice, an effect mitigated by acute toluene exposure. mPFC activity decreased during rewarded trials, with larger decreases following risky/large wins compared with safe/small wins. Toluene-treated animals also had decreased mPFC activity during rewarded trials, but there was no distinction between risky/large wins and safe/small wins. These results provide physiological evidence for mPFC-dependent behavioral deficits caused by toluene. Inhalants (e.g., toluene) are an understudied class of drugs of abuse that cause devastating behavioral and cognitive deficits in humans. Understanding the neurobiological interactions of toluene vapor using animal models is important for developing effective treatment strategies for inhalant addicts. Here we find that toluene vapor reduces behavioral flexibility in rodents making risk/reward-based decisions. The medial prefrontal cortex (mPFC) drives behavioral flexibility during this type of decision-making and we show that toluene reduces the ability of mPFC neurons to track optimal choices as reward probabilities change. Toluene also reduces these neurons' ability to distinguish between small and large rewards. A combination of these factors likely leads to the impaired performance in probabilistic discounting following acute toluene exposure.
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http://dx.doi.org/10.1523/JNEUROSCI.1674-19.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855687PMC
November 2019

Corticotropin-Releasing Factor (CRF) circuit modulation of cognition and motivation.

Neurosci Biobehav Rev 2019 08 15;103:50-59. Epub 2019 Jun 15.

Department of Psychology and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada.

The neuropeptide, corticotropin-releasing factor (CRF), is a key modulator of physiological, endocrine, and behavioral responses during stress. Dysfunction of the CRF system has been observed in stress-related affective disorders including post-traumatic stress disorder, depression, and anxiety. Beyond affective symptoms, these disorders are also characterized by impaired cognition, for which current pharmacological treatments are lacking. Thus, there is a need for pro-cognitive treatments to improve quality of life for individuals suffering from mental illness. In this review, we highlight research demonstrating that CRF elicits potent modulatory effects on higher-order cognition via actions within the prefrontal cortex and subcortical monoaminergic and cholinergic systems. Additionally, we identify questions for future preclinical research on this topic, such as the need to investigate sex differences in the cognitive and microcircuit actions of CRF, and whether CRF may represent a pharmacological target to treat cognitive dysfunction. Addressing these questions will provide new insight into pathophysiology underlying cognitive dysfunction and may lead to improved treatments for neuropsychiatric disorders.
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http://dx.doi.org/10.1016/j.neubiorev.2019.06.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692202PMC
August 2019

Alterations in effort-related decision-making induced by stimulation of dopamine D, D, D, and corticotropin-releasing factor receptors in nucleus accumbens subregions.

Psychopharmacology (Berl) 2019 Sep 10;236(9):2699-2712. Epub 2019 Apr 10.

Department of Psychology and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2136 West Mall, Vancouver, British Columbia, V6T 1Z4, Canada.

Rationale: Nucleus accumbens (NAc) dopamine (DA) plays an integral role in overcoming effort costs, as blockade of D and D receptors reduces the choice of larger, more-costly rewards. Similarly, the stress neuropeptide corticotropin-releasing factor (CRF) modulates DA transmission and mediates stress-induced alterations in effort-related choice.

Objectives: The current study explored how excessive stimulation of different DA receptors within the NAc core and shell alters effort-related decision-making and compared these effects to those induced by CRF stimulation.

Methods: Male Long Evans rats were well-trained on an effort-discounting task wherein they choose between a low-effort/low-reward and a high-effort/high-reward lever where the effort requirement increased over blocks (2-20 presses). Dopamine D (SKF 81297, 0.2-2 μg), D (quinpirole, 1-10 μg), or D (PD 128,907, 1.5-3 μg) receptor agonists, or CRF (0.5 μg), were infused into the NAc core or shell prior to testing.

Results: Stimulation of D receptors with quinpirole in the NAc core or shell markedly reduced the choice of high-effort option and increase choice latencies, without altering preference for larger vs smaller rewards. Stimulation of D or D receptors did not alter choice, although SKF 81297 infusions into the shell reduced response vigor. In comparison, core infusions of CRF flattened the discounting curve, reducing effortful choice when costs were low and increasing it when costs were high.

Conclusions: Excessive stimulation of NAc D receptors has detrimental effects on effort-related decision-making. Furthermore, CRF stimulation induces dissociable effects on decision-making compared with those induced the effects of stimulation of different DA receptors.
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http://dx.doi.org/10.1007/s00213-019-05244-wDOI Listing
September 2019

DREADD-mediated modulation of locus coeruleus inputs to mPFC improves strategy set-shifting.

Neurobiol Learn Mem 2019 05 22;161:1-11. Epub 2019 Feb 22.

Brain Health Institute, Rutgers University/Rutgers Biomedical and Health Sciences, 683 Hoes Lane West, Office 259A, Piscataway, NJ 08854, United States. Electronic address:

Appropriate modification of behavior in response to our dynamic environment is essential for adaptation and survival. This adaptability allows organisms to maximize the utility of behavior-related energy expenditure. Modern theories of locus coeruleus (LC) function implicate a pivotal role for the noradrenergic nucleus in mediating switches between focused behavior during periods of high utility (exploit) versus disengagement of behavior and exploration of other, more rewarding opportunities. Two modes of activity in LC neurons have been characterized as elements in an Adaptive Gain Theory (AGT) of LC function. In this theory, during periods of accurate and focused behavior, LC neurons exhibit task-related phasic bursts. However, as behavioral utility wanes, phasic activity is suppressed and baseline (tonic) impulse activity increases to facilitate exploration. Our experiments sought to exogenously induce an elevated pattern of activity in LC neurons and their medial prefrontal cortical (mPFC) targets to test the tenets of the AGT. This theory posits that tonic activation immediately following a rule change should increase exploration and thereby improve performance on a set-shifting task. Indeed, DREADD mediated stimulation of LC terminals within mPFC decreased trials to reach criterion. However, this effect resulted from improved application of the new rule once the original rule is jettisoned rather than earlier disengagement from the old, ineffective strategy. Such improvements were not seen with global manipulation of LC, consistent with the view that LC-mediated exploration involves specific sub-circuits targeting mPFC. These findings extend our understanding of the role of LC in PFC and flexible behavior.
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http://dx.doi.org/10.1016/j.nlm.2019.02.009DOI Listing
May 2019

Optogenetic Dissection of Temporal Dynamics of Amygdala-Striatal Interplay during Risk/Reward Decision Making.

eNeuro 2018 Nov-Dec;5(6). Epub 2018 Dec 10.

Department of Psychology and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, CANADA, V6T 1Z4.

Decision making often requires weighing costs and benefits of different options that vary in terms of reward magnitude and uncertainty. Previous studies using pharmacological inactivations have shown that the basolateral amygdala (BLA) to nucleus accumbens (NAc) pathway promotes choice towards larger/riskier rewards. Neural activity in BLA and NAc shows distinct, phasic changes in firing prior to choice and following action outcomes, yet, how these temporally-discrete patterns of activity within BLA→NAc circuitry influence choice is unclear. We assessed how optogenetic silencing of BLA terminals in the NAc altered action selection during probabilistic decision making. Rats received intra-BLA infusions of viruses encoding the inhibitory opsin eArchT and were well trained on a probabilistic discounting task, where they chose between smaller/certain rewards and larger rewards delivered in a probabilistic manner, with the odds of obtaining the larger reward changing over a session (50-12.5%). During testing, activity of BLA→NAc inputs were suppressed with 4- to 7-s pulses of light delivered via optic fibers into the NAc during discrete task events: prior to choice or after choice outcomes. Inhibition prior to choice reduced selection of the preferred option, suggesting that during deliberation, BLA→NAc activity biases choice towards preferred rewards. Inhibition during reward omissions increased risky choice during the low-probability block, indicating that activity after non-rewarded actions serves to modify subsequent choice. In contrast, silencing during rewarded outcomes did not reliably affect choice. These data demonstrate how patterns of activity in BLA→NAc circuitry convey different types of information that guide action selection in situations involving reward uncertainty.
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http://dx.doi.org/10.1523/ENEURO.0422-18.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325538PMC
March 2019

Disinhibition of the prefrontal cortex leads to brain-wide increases in neuronal activation that are modified by spatial learning.

Brain Struct Funct 2019 Jan 8;224(1):171-190. Epub 2018 Oct 8.

Graduate Program in Neuroscience, Department of Psychology, Centre for Brain Health, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada.

Deficient prefrontal cortex (PFC) GABA function is hypothesized to play a role in schizophrenia and other psychiatric disorders. In rodents, PFC GABA receptor antagonism produces cognitive and behavioral changes relevant to these disorders, including impaired spatial memory assessed with the traditional working/reference memory radial maze task. This aspect of spatial memory does not depend on PFC, suggesting that deficient PFC GABAergic transmission may interfere with non-PFC-dependent cognitive functions via aberrant increases in PFC output. To test this, we assessed whether PFC GABA antagonism (50 ng bicuculline methbromide) alters neuronal activation in PFC terminal regions, including the striatum, thalamus, hippocampus, amygdala, and cortical regions, of adult male rats using the immediate early gene, c-Fos, as an activity marker. A subset of these animals were also trained and/or tested on the working/reference memory radial maze task. These treatments caused widespread increases in neuronal activation in animals under baseline conditions, with notable exception of the hippocampus. Furthermore, PFC GABA antagonism impaired task performance. In most instances, training and/or testing on the radial maze had no additional effects on neuronal activation. However, in both the hippocampus and rhomboid thalamic nucleus, PFC GABA antagonism caused a selective increase in neuronal activation in animals trained on the maze. These results indicate that deficiencies in PFC GABAergic transmission may have widespread impacts on neuronal activity that may interfere with certain PFC-independent cognitive functions. Furthermore, these alterations in activity are modulated by plasticity induced by spatial learning in the hippocampus and rhomboid thalamic nucleus.
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http://dx.doi.org/10.1007/s00429-018-1769-zDOI Listing
January 2019

Effects of aging on executive functioning and mesocorticolimbic dopamine markers in male Fischer 344 × brown Norway rats.

Neurobiol Aging 2018 12 28;72:134-146. Epub 2018 Aug 28.

Department of Psychology, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address:

Aging is associated with changes in executive functioning and the mesocorticolimbic dopamine system. However, the effects of aging on different forms of behavioral flexibility are not fully characterized. In young (∼5 months) and aged (∼22 months) male Fischer 344 × brown Norway rats, we assessed spatial working memory and different forms of behavioral flexibility using operant tasks: strategy set-shifting (study 1) or probabilistic reversal learning (study 2). We also assessed dopaminergic markers using immunohistochemistry. Compared with young rats, aged rats displayed impairments in working memory. Aged rats also showed nonperseverative impairments in set-shifting, with a subset also showing impairments in initial discrimination learning. In probabilistic reversal learning, aged rats completed more reversals, driven by an increased sensitivity to recent reward and negative feedback. Tyrosine hydroxylase (TH) showed region-specific changes with aging and was correlated with several measures of behavioral flexibility. These data suggest that age-related changes prefrontal cortical function and dopamine synthesis contribute to changes in executive functioning during aging.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.08.020DOI Listing
December 2018

Androgen Regulation of the Mesocorticolimbic System and Executive Function.

Front Endocrinol (Lausanne) 2018 5;9:279. Epub 2018 Jun 5.

Department of Psychology, University of British Columbia, Vancouver, BC, Canada.

Multiple lines of evidence indicate that androgens, such as testosterone, modulate the mesocorticolimbic system and executive function. This review integrates neuroanatomical, molecular biological, neurochemical, and behavioral studies to highlight how endogenous and exogenous androgens alter behaviors, such as behavioral flexibility, decision making, and risk taking. First, we briefly review the neuroanatomy of the mesocorticolimbic system, which mediates executive function, with a focus on the ventral tegmental area (VTA), nucleus accumbens (NAc), medial prefrontal cortex (mPFC), and orbitofrontal cortex (OFC). Second, we present evidence that androgen receptors (AR) and other steroid receptors are expressed in the mesocorticolimbic system. Using sensitive immunohistochemistry and quantitative polymerase chain reaction (qPCR) techniques, ARs are detected in the VTA, NAc, mPFC, and OFC. Third, we describe recent evidence for local androgens ("neuroandrogens") in the mesocorticolimbic system. Steroidogenic enzymes are expressed in mesocorticolimbic regions. Furthermore, following long-term gonadectomy, testosterone is nondetectable in the blood but detectable in the mesocorticolimbic system, using liquid chromatography tandem mass spectrometry. However, the physiological relevance of neuroandrogens remains unknown. Fourth, we review how anabolic-androgenic steroids (AAS) influence the mesocorticolimbic system. Fifth, we describe how androgens modulate the neurochemistry and structure of the mesocorticolimbic system, particularly with regard to dopaminergic signaling. Finally, we discuss evidence that androgens influence executive functions, including the effects of androgen deprivation therapy and AAS. Taken together, the evidence indicates that androgens are critical modulators of executive function. Similar to dopamine signaling, there might be optimal levels of androgen signaling within the mesocorticolimbic system for executive functioning. Future studies should examine the regulation and functions of neurosteroids in the mesocorticolimbic system, as well as the potential deleterious and enduring effects of AAS use.
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http://dx.doi.org/10.3389/fendo.2018.00279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5996102PMC
June 2018

Cooperative and dissociable involvement of the nucleus accumbens core and shell in the promotion and inhibition of actions during active and inhibitory avoidance.

Neuropharmacology 2018 08 22;138:57-71. Epub 2018 May 22.

Department of Psychology and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, B.C., V6T 1Z4, Canada. Electronic address:

The flexible implementation of active and passive strategies to avoid danger is critical to survival. Conversely, the inappropriate allocation of these behaviors may underlie pathological avoidance in neuropsychiatric illnesses. The present study investigated whether these two poles of avoidance may be differentially regulated by subdivsions of the nucleus accumbens, the core (NAcC) and shell (NAcS), which are known to bi-directionally control flexible action selection during reward-seeking. In so doing, we developed a novel cued active/inhibitory avoidance task conducted in operant chambers that entailed presentations of two distinct, 15 s auditory cues. One cue indicated that impending foot-shocks could be avoided by pressing a lever (active avoidance), whereas another cue signaled that shocks could be avoided by withholding presses (inhibitory avoidance). In well-trained rats, pharmacological inactivation of either the NAcC or NAcS impaired active avoidance. In contrast, inhibitory avoidance was disrupted by inactivation of the NAcS, but not NAcC, reflecting a deficit in response-inhibition that manifested as more inhibitory avoidance failures and lever-presses, as well as increased locomotion. Foot-shock sensitivity was unaffected by inactivation of either subregion. In a subsequent experiment, treatment with the monoamine releaser d-amphetamine (1 mg/kg) did not affect active avoidance, but disinhibited lever pressing during inhibitory avoidance trials. These results provide novel insight into the ventral striatal and monoaminergic regulation of flexible response allocation and inhibition that facilitates avoidance behavior and highlight the importance of different subregions of the NAc in action selection during aversively-motivated behaviors.
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http://dx.doi.org/10.1016/j.neuropharm.2018.05.028DOI Listing
August 2018

D-Cycloserine Facilitates Reversal in an Animal Model of Post-traumatic Stress Disorder.

Behav Brain Res 2018 07 23;347:332-338. Epub 2018 Mar 23.

Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA; Ann Arbor Veterans Affairs Hospital, Ann Arbor, MI, USA. Electronic address:

Many psychiatric disorders are associated with cognitive dysfunction that is ineffectively treated by existing pharmacotherapies and which may contribute to poor real-world functioning. D-cycloserine (DCS) is a partial N-methyl-D-aspartate (NMDA) agonist that has attracted attention because of its cognitive enhancing properties, including in people with post-traumatic stress disorder (PTSD). Here, we examined the effect of DCS on reversal learning - a type of cognitive flexibility - following exposure to single prolonged stress (SPS), a rodent model of PTSD. Male Sprague Dawley rats (n = 64) were trained to press levers in an operant chamber, matched for performance and assigned to SPS or control (unstressed) groups. Following SPS, rats received three additional lever press sessions, followed by a side bias test on day three. One day later they learned a response discrimination rule (press left or right lever, opposite to side bias) and on a subsequent day were trained (and tested) for reversal to the opposite lever. DCS (15 mg/kg) or vehicle was administered 30 minutes prior to the reversal session. No between-group differences were found in acquisition or retrieval of the initial rule, but a significant drug x stress interaction on response discrimination reversal indicated that DCS had a greater beneficial effect on SPS rats' cognitive flexibility than it did on performance in controls. These findings add to a growing literature on the beneficial effects of DCS for treating a wide variety of deficits that develop following exposure to extreme stress and may have implications for the development of novel pharmacotherapies for PTSD.
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http://dx.doi.org/10.1016/j.bbr.2018.03.037DOI Listing
July 2018
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