Fundamental Sex Differences in Cocaine-Induced Plasticity of Dopamine D1 Receptor- and D2 Receptor-Expressing Medium Spiny Neurons in the Mouse Nucleus Accumbens Shell.

Background: Cocaine-induced plasticity in the nucleus accumbens shell of males occurs primarily in dopamine D1 receptor-expressing medium spiny neurons (D1R-MSNs), with little if any impact on dopamine D2 receptor-expressing medium spiny neurons (D2R-MSNs). In females, the effect of cocaine on accumbens shell D1R- and D2R-MSN neurophysiology has yet to be reported, nor have estrous cycle effects been accounted for. Methods: We used a 5-day locomotor sensitization paradigm followed by a 10- to 14-day drug-free abstinence period. We then obtained ex vivo whole-cell recordings from fluorescently labeled D1R-MSNs and D2R-MSNs in the nucleus accumbens shell of male and female mice during estrus and diestrus. We examined accumbens shell neuronal excitability as well as miniature excitatory postsynaptic currents (mEPSCs). Results: In females, we observed alterations in D1R-MSN excitability across the estrous cycle similar in magnitude to the effects of cocaine in males. Furthermore, cocaine shifted estrous cycle-dependent plasticity from intrinsic excitability changes in D1R-MSNs to D2R-MSNs. In males, cocaine treatment produced the anticipated drop in D1R-MSN excitability with no effect on D2R-MSN excitability. Cocaine increased mEPSC frequencies and amplitudes in D2R-MSNs from females in estrus and mEPSC amplitudes of D2R-MSNs from females in diestrus. In males, cocaine increased both D1R- and D2R-MSN mEPSC amplitudes with no effect on mEPSC frequencies. Conclusions: Overall, while there are similar cocaine-induced disparities regarding the relative excitability of D1R-MSNs versus D2R-MSNs between the sexes, this is mediated through reduced D1R-MSN excitability in males, whereas it is due to heightened D2R-MSN excitability in females.

The nucleus accumbens shell (NAcSh) is a key brain region involved in motivation and reward. It is primarily composed of dopamine D₁ and D₂ receptor­expressing medium spiny neurons (D1R and D2R neurons). Previous studies in males demonstrated that D1R neurons undergo intrinsic plasticity following cocaine exposure, believed to underlie aspects of drug addiction. We confirmed this effect. It has also been generally assumed that females would show similar responses. However, this does not appear to be true, and our data indicate 2 novel findings. First, under baseline conditions, the estrous cycle produces recurring changes in D1R neuron excitability, with no changes observed in D2R neurons. Second, following cocaine exposure, D1R neuron plasticity is arrested, and D2R neurons begin to show estrous cycle effects on intrinsic excitability. These results indicate profound sex differences in the neurophysiological underpinnings of motivational behaviors including drug addiction.

Physiological acetic acid concentrations from ethanol metabolism stimulate accumbens shell medium spiny neurons via NMDAR activation in a sex-dependent manner.

Recent studies have implicated the ethanol metabolite, acetic acid, as neuroactive, perhaps even more so than ethanol itself. In this study, we investigated sex-specific metabolism of ethanol (1, 2, and 4 g/kg) to acetic acid in vivo to guide electrophysiology experiments in the accumbens shell (NAcSh), a key node in the mammalian reward circuit. There was a sex-dependent difference in serum acetate production, quantified via ion chromatography only at the lowest dose of ethanol (males > females). Ex vivo electrophysiology recordings of NAcSh medium spiny neurons (MSN) in brain slices demonstrated that physiological concentrations of acetic acid (2 mM and 4 mM) increased NAcSh MSN excitability in both sexes. N-methyl-D-aspartate receptor (NMDAR) antagonists, AP5 and memantine, robustly attenuated the acetic acid-induced increase in excitability. Acetic acid-induced NMDAR-dependent inward currents were greater in females compared to males and were not estrous cycle dependent. These findings suggest a novel NMDAR-dependent mechanism by which the ethanol metabolite, acetic acid, may influence neurophysiological effects in a key reward circuit in the brain from ethanol consumption. Furthermore, these findings also highlight a specific sex-dependent sensitivity in females to acetic acid-NMDAR interactions. This may underlie their more rapid advancement to alcohol use disorder and increased risk of alcohol related neurodegeneration compared to males.

Sex differences in mouse infralimbic cortex projections to the nucleus accumbens shell.

BACKGROUND: The nucleus accumbens (NAc) is an important region in motivation and reward. Glutamatergic inputs from the infralimbic cortex (ILC) to the shell region of the NAc (NAcSh) have been implicated in driving the motivation to seek reward through repeated action-based behavior. While this has primarily been studied in males, observed sex differences in motivational circuitry and behavior suggest that females may be more sensitive to rewarding stimuli. These differences have been implicated for the observed vulnerability in women to substance use disorders. METHODS: We used an optogenetic self-stimulation task in addition to ex vivo electrophysiological recordings of NAcSh neurons in mouse brain slices to investigate potential sex differences in ILC-NAcSh circuitry in reward-seeking behavior. Glutamatergic neurons in the ILC were infected with an AAV delivering DNA encoding for channelrhodopsin. Entering the designated active corner of an open field arena resulted in photostimulation of the ILC terminals in the NAcSh. Self-stimulation occurred during two consecutive days of testing over three consecutive weeks: first for 10 Hz, then 20 Hz, then 30 Hz. Whole-cell recordings of medium spiny neurons in the NAcSh assessed both optogenetically evoked local field potentials and intrinsic excitability. RESULTS: Although both sexes learned to seek the active zone, within the first day, females entered the zone more than males, resulting in a greater amount of photostimulation. Increasing the frequency of optogenetic stimulation amplified female reward-seeking behavior. Males were less sensitive to ILC stimulation, with higher frequencies and repeated days required to increase male reward-seeking behavior. Unexpectedly, ex vivo optogenetic local field potentials in the NAcSh were greater in slices from male animals. In contrast, female medium-spiny neurons (MSNs) displayed significantly greater intrinsic neuronal excitability. CONCLUSIONS: Taken together, these data indicate that there are sex differences in the motivated behavior driven by glutamate within the ILC-NAcSh circuit. Though glutamatergic signaling was greater in males, heightened intrinsic excitability in females appears to drive this sex difference.

The shell region of the nucleus accumbens (NAcSh) is involved in motivation and reward. It receives excitatory glutamatergic inputs from multiple brain regions. One specific region is the infralimbic cortex (ILC), which when activated, influences reward-seeking behavior. While previous research has focused on males, there are inherent sex differences in reward circuitry and reward-seeking behavior. Using an optogenetic self-stimulation task, in addition to ex vivo electrophysiological recordings, we found inherent sex differences in the ILC-NAcSh circuit in behavioral output, synaptic strength, and intrinsic neurophysiology. Female mice showed more robust reward-seeking behavior. Increasing the frequency of stimulation intensified this behavior in females, while males required higher frequencies and repeated testing days to increase their reward-seeking behavior. Surprisingly, optogenetically stimulating the ILC terminals in the NAcSh in brain slices resulted in stronger responses in males. More consistent with the behavioral data, female MSNs displayed higher intrinsic excitability. Our results suggest that there are sex differences in motivated behavior, driven by glutamatergic signaling in the ILC-NAc circuit. Despite stronger ILC-based glutamatergic signaling in males, heightened intrinsic excitability of MSNs in females seems to be the driving force behind this sex difference in reward-seeking behavior. These findings contribute to our understanding of the neural mechanisms behind sex-based differences in motivation and their potential implications for substance use disorders.

Deep Brain Stimulation for Substance Use Disorders? An Exploratory Qualitative Study of Perspectives of People Currently in Treatment.

OBJECTIVE: Although previous studies have discussed the promise of deep brain stimulation (DBS) as a possible treatment for substance use disorders (SUDs) and collected researcher perspectives on possible ethical issues surrounding it, none have consulted people with SUDs themselves. We addressed this gap by interviewing people with SUDs. METHODS: Participants viewed a short video introducing DBS, followed by a 1.5-hour semistructured interview on their experiences with SUDs and their perspective on DBS as a possible treatment option. Interviews were analyzed by multiple coders who iteratively identified salient themes. RESULTS: We interviewed 20 people in 12-step-based, inpatient treatment programs (10 [50%] White/Caucasian, 7 Black/African American [35%], 2 Asian [10%], 1 Hispanic/Latino [5%], and 1 [5%] Alaska Native/American Indian; 9 women [45%], 11 men [55%]). Interviewees described a variety of barriers they currently faced through the course of their disease that mirrored barriers often associated with DBS (stigma, invasiveness, maintenance burdens, privacy risks) and thus made them more open to the possibility of DBS as a future treatment option. CONCLUSIONS: Individuals with SUDs gave relatively less weight to surgical risks and clinical burdens associated with DBS than previous surveys of provider attitudes anticipated. These differences derived largely from their experiences living with an often-fatal disease and encountering limitations of current treatment options. These findings support the study of DBS as a treatment option for SUDs, with extensive input from people with SUDs and advocates.

Physiological acetic acid concentrations from ethanol metabolism stimulate accumbens shell neurons via NMDAR activation in a sex-dependent manner.

Recent studies have implicated the ethanol metabolite, acetic acid, as neuroactive, perhaps even more so than ethanol itself. In this study, we investigated sex-specific metabolism of ethanol (1, 2, and 4g/kg) to acetic acid in vivo to guide electrophysiology experiments in the accumbens shell (NAcSh), a key node in the mammalian reward circuit. There was a sex-dependent difference in serum acetate production, quantified via ion chromatography only at the lowest dose of ethanol (males>females). Ex vivo electrophysiology recordings of NAcSh neurons in brain slices demonstrated that physiological concentrations of acetic acid (2 mM and 4 mM) increased NAcSh neuronal excitability in both sexes. N -methyl- D -aspartate receptor (NMDAR) antagonists, AP5, and memantine robustly attenuated the acetic acid-induced increase in excitability. Acetic acid-induced NMDAR-dependent inward currents were greater in females compared to males. These findings suggest a novel NMDAR-dependent mechanism by which the ethanol metabolite, acetic acid, may influence neurophysiological effects in a key reward circuit in the brain.

Sex Differences in Cocaine Sensitization Vary by Mouse Strain.

INTRODUCTION: Preclinical literature, frequently utilizing rats, suggests females display a more rapid advancement of substance abuse and a greater risk of relapse following drug abstinence. In clinical populations, it is less clear as to what extent biological sex is a defining variable in the acquisition and maintenance of substance use. Even without considering environmental experiences, genetic factors are presumed to critically influence the vulnerability to addiction. Genetically diverse mouse models provide a robust tool to examine the interactions between genetic background and sex differences in substance abuse. METHODS: We explored mouse strain variability in male versus female behavioral sensitization to cocaine. Locomotor sensitization was observed following 5 consecutive days of subcutaneous cocaine across three genetically different mice strains: C57BL/6J, B6129SF2/J, and Diversity Outbred (DO/J). RESULTS: Sex differences in cocaine locomotor sensitization were dependent on mouse strain. Specifically, we observed opposing sex differences in locomotor sensitization, with male C57BL/6J and female B6129SF2/J mice displaying heightened activity compared to their opposite sex counterparts. Conversely, no sex differences were observed in the DO/J mice. Acute cocaine administration resulted in locomotor differences across strains in male, but not female, mice. The magnitude of sensitization (or lack thereof) also varied by genetic background. CONCLUSIONS: While sex differences in drug addiction may be observed, these effects can be mitigated, or even reversed, depending on genetic background. The clinical implications are that in the absence of understanding the genetic variables underlying vulnerability to addiction, sex provides little information regarding the predisposition of an individual to drug abuse.

A quadruple dissociation of reward-related behaviour in mice across excitatory inputs to the nucleus accumbens shell.

The nucleus accumbens shell (NAcSh) is critically important for reward valuations, yet it remains unclear how valuation information is integrated in this region to drive behaviour during reinforcement learning. Using an optogenetic spatial self-stimulation task in mice, here we show that contingent activation of different excitatory inputs to the NAcSh change expression of different reward-related behaviours. Our data indicate that medial prefrontal inputs support place preference via repeated actions, ventral hippocampal inputs consistently promote place preferences, basolateral amygdala inputs produce modest place preferences but as a byproduct of increased sensitivity to time investments, and paraventricular inputs reduce place preferences yet do not produce full avoidance behaviour. These findings suggest that each excitatory input provides distinct information to the NAcSh, and we propose that this reflects the reinforcement of different credit assignment functions. Our finding of a quadruple dissociation of NAcSh input-specific behaviours provides insights into how types of information carried by distinct inputs to the NAcSh could be integrated to help drive reinforcement learning and situationally appropriate behavioural responses.

Sunk cost sensitivity during change-of-mind decisions is informed by both the spent and remaining costs.

Sunk cost sensitivity describes escalating decision commitment with increased spent resources. On neuroeconomic foraging tasks, mice, rats, and humans show similar escalations from sunk costs while quitting an ongoing countdown to reward. In a new analysis taken across computationally parallel foraging tasks across species and laboratories, we find that these behaviors primarily occur on choices that are economically inconsistent with the subject's other choices, and that they reflect not only the time spent, but also the time remaining, suggesting that these are change-of-mind re-evaluation processes. Using a recently proposed change-of-mind drift-diffusion model, we find that the sunk cost sensitivity in this model arises from decision-processes that directly take into account the time spent (costs sunk). Applying these new insights to experimental data, we find that sensitivity to sunk costs during re-evaluation decisions depends on the information provided to the subject about the time spent and the time remaining.

The ethanol metabolite acetic acid activates mouse nucleus accumbens shell medium spiny neurons.

Although ethanol consumption leads to an array of neurophysiological alterations involving the neural circuits for reward, the underlying mechanisms remain unclear. Acetic acid is a major metabolite of ethanol with high bioactivity and potentially significant pharmacological importance in regulating brain function. Yet, the impact of acetic acid on reward circuit function has not been well explored. Given the rewarding properties associated with ethanol consumption, we investigated the acute effects of ethanol and/or acetic acid on the neurophysiological function of medium spiny neurons of the nucleus accumbens shell, a key node in the mammalian reward circuit. We find that acetic acid, but not ethanol, provided a rapid and robust boost in neuronal excitability at physiologically relevant concentrations, whereas both compounds enhanced glutamatergic synaptic activity. These effects were consistent across both sexes in C57BL/6J mice. Overall, our data suggest acetic acid is a promising candidate mediator for ethanol effects on mood and motivation that deserves further investigation.NEW & NOTEWORTHY Ethanol consumption disrupts many neurophysiological processes leading to alterations in behavior and physiological function. The possible involvement of acetic acid, produced via ethanol metabolism, has been insufficiently explored. Here, we demonstrate that acetic acid contributes to rapid neurophysiological alterations in the accumbens shell. These findings raise the interesting possibility that ethanol may serve as a prodrug-generating acetic acid as a metabolite-that may influence ethanol consumption-associated behaviors and physiological responses by altering neurophysiological function.

Caveolin-1 regulates medium spiny neuron structural and functional plasticity.

RATIONALE: Caveolin-1 (CAV1) is a structural protein critical for spatial organization of neuronal signaling molecules. Whether CAV1 is required for long-lasting neuronal plasticity remains unknown. OBJECTIVE AND METHODS: We sought to examine the effects of CAV1 knockout (KO) on functional plasticity and hypothesized that CAV1 deficiency would impact drug-induced long-term plasticity in the nucleus accumbens (NAc). We first examined cell morphology of NAc medium spiny neurons in a striatal/cortical co-culture system before moving in vivo to study effects of CAV1 KO on cocaine-induced plasticity. Whole-cell patch-clamp recordings were performed to determine effects of chronic cocaine (15 mg/kg) on medium spiny neuron excitability. To test for deficits in behavioral plasticity, we examined the effect of CAV1 KO on locomotor sensitization. RESULTS: Disruption of CAV1 expression leads to baseline differences in medium spiny neuron (MSN) structural morphology, such that MSNs derived from CAV1 KO animals have increased dendritic arborization when cultured with cortical neurons. The effect was dependent on phospholipase C and cell-type intrinsic loss of CAV1. Slice recordings of nucleus accumbens shell MSNs revealed that CAV1 deficiency produces a loss of neuronal plasticity. Specifically, cocaine-induced firing rate depression was absent in CAV1 KO animals, whereas baseline electrophysiological properties were similar. This was reflected by a loss of cocaine-mediated behavioral sensitization in CAV1 KO animals, with unaffected baseline locomotor responsiveness. CONCLUSIONS: This study highlights a critical role for nucleus accumbens CAV1 in plasticity related to the administration of drugs of abuse.

Dopamine-Evoked Synaptic Regulation in the Nucleus Accumbens Requires Astrocyte Activity.

Dopamine is involved in physiological processes like learning and memory, motor control and reward, and pathological conditions such as Parkinson's disease and addiction. In contrast to the extensive studies on neurons, astrocyte involvement in dopaminergic signaling remains largely unknown. Using transgenic mice, optogenetics, and pharmacogenetics, we studied the role of astrocytes on the dopaminergic system. We show that in freely behaving mice, astrocytes in the nucleus accumbens (NAc), a key reward center in the brain, respond with Ca2+ elevations to synaptically released dopamine, a phenomenon enhanced by amphetamine. In brain slices, synaptically released dopamine increases astrocyte Ca2+, stimulates ATP/adenosine release, and depresses excitatory synaptic transmission through activation of presynaptic A1 receptors. Amphetamine depresses neurotransmission through stimulation of astrocytes and the consequent A1 receptor activation. Furthermore, astrocytes modulate the acute behavioral psychomotor effects of amphetamine. Therefore, astrocytes mediate the dopamine- and amphetamine-induced synaptic regulation, revealing a novel cellular pathway in the brain reward system.

Cell-type and region-specific nucleus accumbens AMPAR plasticity associated with morphine reward, reinstatement, and spontaneous withdrawal.

Despite evidence that morphine-related pathologies reflect adaptations in NAc glutamate signaling, substantial gaps in basic information remain. The current study examines the impact of non-contingent acute, repeated, and withdrawal-inducing morphine dosing regimens on glutamate transmission in D1- or D2-MSNs in the nucleus accumbens shell (NAcSh) and core (NAcC) sub-regions in hopes of identifying excitatory plasticity that may contribute to unique facets of opioid addiction-related behavior. Following an acute morphine injection (10 mg/kg), average miniature excitatory postsynaptic current (mEPSC) amplitude mediated by AMPA-type glutamate receptors was increased at D1-MSNs in the both the NAcShl and NAcC, whereas only the frequency of events was elevated at D2-MSNs in the NAcSh. In contrast, spontaneous somatic withdrawal induced by escalating dose of repeated morphine twice per day (20, 40, 60, 80, 100 mg/kg) enhanced mEPSC frequency specifically at D2-MSNs in the NAcSh. Similar to previous findings, excitatory drive was elevated at NAcSh D1-MSNs after 10-14 days home cage abstinence. Following abstinence, an acute drug re-exposure produced a rapid and enduring endocytosis of GluA2-containing AMPARs at D1-MSNs in the shell, that when blocked by an intra-NAc shell infusion of the Tat-GluA23Y peptide, increased reinstatement of morphine place preference-a phenomenon distinctly different than effects previously found with cocaine. The present study is the first to directly identify unique circuit specific adaptations in NAc glutamate synaptic transmission associated with morphine-related acute reward and somatic withdrawal as well as post-abstinence short-term plasticity. Moreover, while differing classes of abused drugs (i.e., psychostimulants and opioids) produce seemingly similar bidirectional plasticity in the NAc following drug re-exposure, our findings indicate this plasticity has distinct behavioral consequences.

Opioid-Mediated Astrocyte-Neuron Signaling in the Nucleus Accumbens.

Major hallmarks of astrocyte physiology are the elevation of intracellular calcium in response to neurotransmitters and the release of neuroactive substances (gliotransmitters) that modulate neuronal activity. While µ-opioid receptor expression has been identified in astrocytes of the nucleus accumbens, the functional consequences on astrocyte-neuron communication remains largely unknown. The present study has investigated the astrocyte responsiveness to µ-opioid signaling and the regulation of gliotransmission in the nucleus accumbens. Through the combination of calcium imaging and whole-cell patch clamp electrophysiology in brain slices, we have found that µ-opioid receptor activation in astrocytes elevates astrocyte cytoplasmic calcium and stimulates the release of the gliotransmitter glutamate, which evokes slow inward currents through the activation of neuronal N-methyl-D-aspartate (NMDA) receptors. These results indicate the existence of molecular mechanisms underlying opioid-mediated astrocyte-neuron signaling in the nucleus accumbens.

Synaptic Depotentiation and mGluR5 Activity in the Nucleus Accumbens Drive Cocaine-Primed Reinstatement of Place Preference.

Understanding the neurobiological processes that incite drug craving and drive relapse has the potential to help target efforts to treat addiction. The NAc serves as a critical substrate for reward and motivated behavior, in part due to alterations in excitatory synaptic strength within cortical-accumbens pathways. The present studies investigated a causal link between cocaine-induced reinstatement of conditioned place preference and rapid reductions of cocaine-dependent increases in NAc shell synaptic strength in male mice. Cocaine-conditioned place preference behavior and ex vivo whole-cell electrophysiology showed that cocaine-primed reinstatement and synaptic depotentiation were disrupted by inhibiting AMPAR internalization via intra-NAc shell infusion of a Tat-GluA23Y peptide. Furthermore, reinstatement was driven by an mGluR5-dependent reduction in AMPAR signaling. Intra-NAc shell infusion of the mGluR5 antagonist MTEP blocked cocaine-primed reinstatement and corresponding depotentiation, whereas infusion of the mGluR5 agonist CHPG itself promoted reinstatement and depotentiated synaptic strength in the NAc shell. Optogenetic examination of circuit-specific plasticity showed that inhibition of infralimbic cortical input to the NAc shell blocked cocaine-primed reinstatement, whereas low-frequency stimulation (10 Hz) of this pathway in the absence of cocaine triggered a reduction in synaptic strength akin to that observed with cocaine, and was sufficient to promote reinstatement in the absence of a cocaine challenge. These data support a model in which mGluR5-mediated reduction in GluA2-containing AMPARs at NAc shell synapses receiving input from the infralimbic cortex is a critical factor in triggering reinstatement of cocaine-primed conditioned approach behavior.SIGNIFICANCE STATEMENT These studies identified a sequence of neural events whereby reexposure to cocaine activates a signaling cascade that alters synaptic strength in the NAc shell and triggers a behavioral response driven by a drug-associated memory.

Beyond simple tests of value: measuring addiction as a heterogeneous disease of computation-specific valuation processes.

Addiction is considered to be a neurobiological disorder of learning and memory because addiction is capable of producing lasting changes in the brain. Recovering addicts chronically struggle with making poor decisions that ultimately lead to relapse, suggesting a view of addiction also as a neurobiological disorder of decision-making information processing. How the brain makes decisions depends on how decision-making processes access information stored as memories in the brain. Advancements in circuit-dissection tools and recent theories in neuroeconomics suggest that neurally dissociable valuation processes access distinct memories differently, and thus are uniquely susceptible as the brain changes during addiction. If addiction is to be considered a neurobiological disorder of memory, and thus decision-making, the heterogeneity with which information is both stored and processed must be taken into account in addiction studies. Addiction etiology can vary widely from person to person. We propose that addiction is not a single disease, nor simply a disorder of learning and memory, but rather a collection of symptoms of heterogeneous neurobiological diseases of distinct circuit-computation-specific decision-making processes.

Sensitivity to "sunk costs" in mice, rats, and humans.

Sunk costs are irrecoverable investments that should not influence decisions, because decisions should be made on the basis of expected future consequences. Both human and nonhuman animals can show sensitivity to sunk costs, but reports from across species are inconsistent. In a temporal context, a sensitivity to sunk costs arises when an individual resists ending an activity, even if it seems unproductive, because of the time already invested. In two parallel foraging tasks that we designed, we found that mice, rats, and humans show similar sensitivities to sunk costs in their decision-making. Unexpectedly, sensitivity to time invested accrued only after an initial decision had been made. These findings suggest that sensitivity to temporal sunk costs lies in a vulnerability distinct from deliberation processes and that this distinction is present across species.

Extinction and Reinstatement of Cocaine-seeking in Self-administering Mice is Associated with Bidirectional AMPAR-mediated Plasticity in the Nucleus Accumbens Shell.

Experience-dependent synaptic plasticity is an important component of both learning and motivational disturbances found in addicted individuals. Here, we investigated the role of cocaine experience-dependent plasticity at excitatory synapses in the nucleus accumbens shell (NAcSh) in relapse-related behavior in mice with a history of volitional cocaine self-administration. Using an extinction/reinstatement paradigm of cocaine-seeking behavior, we demonstrate that cocaine-experienced mice with extinguished cocaine-seeking behavior show potentiation of synaptic strength at excitatory inputs onto NAcSh medium spiny neurons (MSNs). Conversely, we found that exposure to various distinct types of reinstating stimuli (cocaine, cocaine-associated cues, yohimbine "stress") after extinction can produce a relative depotentiation of NAcSh synapses that is strongly associated with the magnitude of cocaine-seeking behavior exhibited in response to these challenges. Furthermore, we show that these effects are due to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-specific mechanisms that differ depending on the nature and context of the reinstatement-inducing stimuli. Together, our findings identify common themes as well as differential mechanisms that are likely important for the ability of diverse environmental stimuli to drive relapse to addictive-like cocaine-seeking behavior.

Prolonged abstinence from cocaine or morphine disrupts separable valuations during decision conflict.

Neuroeconomic theories propose changes in decision making drive relapse in recovering drug addicts, resulting in continued drug use despite stated wishes not to. Such conflict is thought to arise from multiple valuation systems dependent on separable neural components, yet many neurobiology of addiction studies employ only simple tests of value. Here, we tested in mice how prolonged abstinence from different drugs affects behavior in a neuroeconomic foraging task that reveals multiple tests of value. Abstinence from repeated cocaine and morphine disrupts separable decision-making processes. Cocaine alters deliberation-like behavior prior to choosing a preferred though economically unfavorable offer, while morphine disrupts re-evaluations after rapid initial decisions. These findings suggest that different drugs have long-lasting effects precipitating distinct decision-making vulnerabilities. Our approach can guide future refinement of decision-making behavioral paradigms and highlights how grossly similar behavioral maladaptations may mask multiple underlying, parallel, and dissociable processes that treatments for addiction could potentially target.

Mice learn to avoid regret.

Regret can be defined as the subjective experience of recognizing that one has made a mistake and that a better alternative could have been selected. The experience of regret is thought to carry negative utility. This typically takes two distinct forms: augmenting immediate postregret valuations to make up for losses, and augmenting long-term changes in decision-making strategies to avoid future instances of regret altogether. While the short-term changes in valuation have been studied in human psychology, economics, neuroscience, and even recently in nonhuman-primate and rodent neurophysiology, the latter long-term process has received far less attention, with no reports of regret avoidance in nonhuman decision-making paradigms. We trained 31 mice in a novel variant of the Restaurant Row economic decision-making task, in which mice make decisions of whether to spend time from a limited budget to achieve food rewards of varying costs (delays). Importantly, we tested mice longitudinally for 70 consecutive days, during which the task provided their only source of food. Thus, decision strategies were interdependent across both trials and days. We separated principal commitment decisions from secondary reevaluation decisions across space and time and found evidence for regret-like behaviors following change-of-mind decisions that corrected prior economically disadvantageous choices. Immediately following change-of-mind events, subsequent decisions appeared to make up for lost effort by altering willingness to wait, decision speed, and pellet consumption speed, consistent with past reports of regret in rodents. As mice were exposed to an increasingly reward-scarce environment, we found they adapted and refined distinct economic decision-making strategies over the course of weeks to maximize reinforcement rate. However, we also found that even without changes in reinforcement rate, mice transitioned from an early strategy rooted in foraging to a strategy rooted in deliberation and planning that prevented future regret-inducing change-of-mind episodes from occurring. These data suggest that mice are learning to avoid future regret, independent of and separate from reinforcement rate maximization.

Altering gain of the infralimbic-to-accumbens shell circuit alters economically dissociable decision-making algorithms.

The nucleus accumbens shell (NAcSh) is involved in reward valuation. Excitatory projections from infralimbic cortex (IL) to NAcSh undergo synaptic remodeling in rodent models of addiction and enable the extinction of disadvantageous behaviors. However, how the strength of synaptic transmission of the IL-NAcSh circuit affects decision-making information processing and reward valuation remains unknown, particularly because these processes can conflict within a given trial and particularly given recent data suggesting that decisions arise from separable information-processing algorithms. The approach of many neuromodulation studies is to disrupt information flow during on-going behaviors; however, this limits the interpretation of endogenous encoding of computational processes. Furthermore, many studies are limited by the use of simple behavioral tests of value which are unable to dissociate neurally distinct decision-making algorithms. We optogenetically altered the strength of synaptic transmission between glutamatergic IL-NAcSh projections in mice trained on a neuroeconomic task capable of separating multiple valuation processes. We found that induction of long-term depression in these synapses produced lasting changes in foraging processes without disrupting deliberative processes. Mice displayed inflated reevaluations to stay when deciding whether to abandon continued reward-seeking investments but displayed no changes during initial commitment decisions. We also developed an ensemble-level measure of circuit-specific plasticity that revealed individual differences in foraging valuation tendencies. Our results demonstrate that alterations in projection-specific synaptic strength between the IL and the NAcSh are capable of augmenting self-control economic valuations within a particular decision-making modality and suggest that the valuation mechanisms for these multiple decision-making modalities arise from different circuits.