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Those with diabetes mellitus are at high-risk of developing psychiatric disorders, especially mood disorders, yet the link between hyperglycemia and altered motivation has not been thoroughly explored. Here, we characterized value-based decision-making behavior of a streptozocin-induced diabetic mouse model on Restaurant Row, a naturalistic neuroeconomic foraging paradigm capable of behaviorally capturing multiple decision systems known to depend on dissociable neural circuits. Mice made self-paced choices on a daily limited time-budget, accepting or rejecting reward offers based on cost (delays cued by tone pitch) and subjective value (flavors), in a closed-economy system tested across months. We found streptozocin-treated mice disproportionately undervalued less-preferred flavors and inverted their meal-consumption patterns shifted toward a more costly strategy overprioritizing high-value rewards. These foraging behaviors were driven by impairments in multiple decision-making processes, including the ability to deliberate when engaged in conflict and cache the value of the passage of time as sunk costs. Surprisingly, diabetes-induced changes in motivation depended not only on the type of choice being made, but also on the salience of reward-scarcity in the environment. These findings suggest that complex relationships between metabolic dysfunction and dissociable valuation algorithms underlying unique cognitive heuristics and sensitivity to opportunity costs can disrupt distinct computational processes leading to comorbid psychiatric vulnerabilities. A neuroeconomic approach to characterize decision-making behavior reveals alterations in distinct valuation algorithms in a mouse model of diabetes, shedding light on the interaction between metabolic disorders, energy balance, and cognitive heuristics.

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.

Biological sex as a defining variable in drug sensitivity remains poorly understood. Here, we combine behavioral and electrophysiological analyses to examine the influence of sex and gonadal hormones on cocaine-induced psychomotor sensitization and nucleus accumbens shell (NAcSh) plasticity in the prominent C57BL/6J mouse strain. Males exhibited greater cocaine-evoked locomotor activity than females; castration attenuated responses, whereas ovariectomy enhanced them. This behavioral phenotype is opposite to what occurs in rats. A 10-14 day abstinence period abolished the sex difference in intact animals, and gonadectomy reduced cocaine-induced behavioral plasticity. Recordings from 309 medium spiny neurons revealed sex-dependent NAcSh plasticity. In males, cocaine decreased neuronal excitability, while in females it induced estrous cycle-dependent plasticity characterized by reduced excitability during diestrus relative to estrus. These effects were driven by cocaine-induced modulation of voltage-gated sodium channels. Cocaine potentiated glutamatergic strength in males but elicited estrous cycle-dependent depotentiation in females. These adaptations in excitability and glutamatergic strength were abolished by gonadectomy, and paralleled diminished behavioral plasticity during abstinence. These data illustrate that biological sex and hormonal milieu critically shape cocaine-induced plasticity, offering a more nuanced framework than the traditional notion of heightened female sensitivity to drugs of abuse.

Although chronic stress increases the risk for depression, only a subset of exposed individuals develop psychiatric illness. The biological mechanisms that protect against depression remain incompletely understood, particularly at the molecular level. Here, we identify a transcriptional network in the nucleus accumbens (NAc), a central brain reward region, that supports stress resilience in both sexes and demonstrate the causal contribution of key hub genes. Using chronic social defeat stress, RNA-seq, and co-expression network analysis, we find sex-specific but overlapping gene modules linked to resilience, anchored by shared hub genes embedded within a common network architecture. Overexpression of these hub genes in stress-naive mice confers stress protection and induces a transcriptional state that is discrete from both susceptible and resilient profiles. These findings position resilience as a structured and targetable molecular phenotype and provide a basis for investigating sex-informed mechanisms of stress adaptation.

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.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.

Those with diabetes mellitus are at high-risk of developing psychiatric disorders, yet the link between hyperglycemia and alterations in motivated behavior has not been explored in detail. We characterized value-based decision-making behavior of a streptozocin-induced diabetic mouse model on a naturalistic neuroeconomic foraging paradigm called Restaurant Row. Mice made self-paced choices while on a limited time-budget accepting or rejecting reward offers as a function of cost (delays cued by tone-pitch) and subjective value (flavors), tested daily in a closed-economy system across months. We found streptozocin-treated mice disproportionately undervalued less-preferred flavors and inverted their meal-consumption patterns shifted toward a more costly strategy that overprioritized high-value rewards. We discovered these foraging behaviors were driven by impairments in multiple decision-making systems, including the ability to deliberate when engaged in conflict and cache the value of the passage of time in the form of sunk costs. Surprisingly, diabetes-induced changes in behavior depended not only on the type of choice being made but also the salience of reward-scarcity in the environment. These findings suggest complex relationships between glycemic regulation and dissociable valuation algorithms underlying unique cognitive heuristics and sensitivity to opportunity costs can disrupt fundamentally distinct computational processes and could give rise to psychiatric vulnerabilities.

Cocaine-induced plasticity in the nucleus accumbens shell of males occurs primarily in D1 dopamine receptor expressing neurons (D1-MSNs), with little if any impact on D2 dopamine receptor neurons (D2-MSNs). Using ex vivo whole cell recordings in male and female mice, we observe alterations in D1-MSN excitability across the estrous cycle similar in magnitude to the actions of cocaine in males. Furthermore, cocaine shifts estrous cycle-dependent plasticity from intrinsic excitability changes in D1-MSNs to D2-MSNs. Overall, while there are similar cocaine-induced disparities regarding the relative excitability of D1-MSN versus D2-MSN between the sexes, in males this is mediated through reduced D1-MSN excitability, whereas in females it is due to heightened D2-MSN excitability.