Compulsive actions are typically thought to reflect the dominance of habits over goal-directed action. To address this, we mimicked the striatal neuroinflammation that is frequently exhibited in individuals with compulsive disorders in rats, by injecting the endotoxin lipopolysaccharide into the posterior dorsomedial striatum, and assessed the consequences for behavioural control. Surprisingly, this manipulation caused rats to acquire and maintain goal-directed actions under conditions that would otherwise produce habits. Immunohistochemical analyses indicated that these behaviours were a result of astrocytic proliferation. To probe this further, we chemogenetically activated the Gi-pathway in striatal astrocytes, which altered the firing properties of nearby medium spiny neurons and modulated goal-directed action control. Together, results show that striatal neuroinflammation is sufficient to bias action selection toward excessive goal-directed control via dysregulated astrocyte function. If translatable, our findings suggest that, contrary to conventional views, individuals with striatal neuroinflammation might be more prone to maladaptive goal-directed actions than habits, and future interventions should aim to restore appropriate action control.

Hippocampal neuroinflammation is present in multiple diseases and disorders that impact motivated behaviour in a sex-specific manner, but whether neuroinflammation alone is sufficient to disrupt such behaviour is unknown. We investigated this question here using mice. First, the application of an endotoxin to primary cultures containing only hippocampal neurons did not affect their activation. However, when the same endotoxin was applied to mixed neuronal/glial cultures it did increase neuronal activation, providing initial indications of how it might be able to effect behavioural change. We next demonstrated neuroinflammatory effects on behaviour directly, demonstrating that intra-hippocampal administration of the same endotoxin increased locomotor activity and accelerated goal-directed learning in both male and female mice. In contrast, hippocampal neuroinflammation caused sex-specific disruptions to the acquisition of instrumental actions and to Pavlovian food-approach memories. Finally, we showed that hippocampal neuroinflammation had a sexually dimorphic effect on neuronal activation: increasing it in females and decreasing it in males.

Research from human and animal studies has found that relapse to compulsive action can be provoked by exposure to certain contexts. However, most of these data have been derived from experiments involving a single active response, and the context-specificity of relapse in situations involving choice between multiple actions and outcomes is less well-understood. We thus investigated how outcome-selective reinstatement involving choice between multiple actions was affected by altering the physical context in rats. In Experiment 1, rats were trained over 6 days to press a left lever for one food outcome (pellets or sucrose) and a right lever for the other outcome. Then, rats received an extinction session in either the same context (A) as lever press training, or in a different context (B). Rats were tested immediately (5 minutes) after extinction in Context A or B such that there were four groups in total: AAA, ABB, ABA, and AAB. Testing consisted of unsignalled presentations of pellet and sucrose outcomes, and selective reinstatement was intact if these presentations reinstated responding on the same lever that earned the outcome during training, e.g. pellet delivery should reinstate responding on the pellet lever. This result (Reinstated > Nonreinstated) was observed for rats in group AAA and ABB, but not rats in groups ABA and AAB. Experiment 2 was conducted identically, except that rats received two extinction sessions over two days and tested one day later. This time, all groups demonstrated intact outcome-selective reinstatement regardless of context. Analysis of c-Fos expression in several brain regions revealed that only c-Fos expression in the posterior dorsomedial striatum (pDMS) was related to intact reinstatement performance. Overall, these results suggest that outcome-selective reinstatement is partially context-dependent, and that intact reinstatement is related to neuronal activity in the pDMS. Highlights Outcome-selective reinstatement is partially context-dependent Outcome-selective reinstatement is entirely context-independent after multiple extinction sessions Outcome-selective reinstatement increases c-Fos expression in dorsomedial striatum c-Fos expression in orbitofrontal cortex and dorsal hippocampus is unaffected by selective reinstatement.

Neuropsychiatric disorders represent a significant global health burden. Despite decades of research, current treatments typically provide only symptomatic relief, rather than addressing the underlying mechanisms of these conditions. Historically, research focused on the dopaminergic and serotonergic systems, which are deeply involved in the pathophysiology of many mental health disorders, including depression, schizophrenia, anxiety, autism spectrum disorder (ASD), and different substance use disorders, including alcohol use disorder (AUD). However, therapies targeting these systems have limitations, often only producing partial symptom relief plus compliance‐limiting side effects. This highlights the need for improved treatments that may emerge from a broader understanding of the neurobiological bases of these conditions, especially neurochemical systems beyond dopamine and serotonin. Additional monoamines (e.g., histamine, acetylcholine, norepinephrine), neurolipid systems (e.g., endocannabinoids), and diverse signaling molecules such as neuropeptides, trace amines, and cytokines are increasingly recognized as key players in the dysfunction of neural circuits. In this review, which originated from the International Society for Neurochemistry (ISN)/Journal of Neurochemistry 5th Flagship School in October 2024 held in Naxos, Greece, we describe the importance of these neuromodulatory systems in the pathophysiology of select neuropsychiatric disorders, discuss their potential as targets for therapeutic intervention, exploring how they may offer more effective, mechanism‐based treatments. We also highlight recent clinical trials, underscoring the progress in advancing towards clinical application, as well as sex‐specific neurobiological differences, a historically overlooked, yet fundamental determinant of the pathophysiology of neuropsychiatric disorders. We propose that expanding our focus beyond traditional monoamines offers a promising avenue for the development of new, disease‐modifying treatments that can more effectively address the underlying causes of neuropsychiatric disorders. By targeting these pathways, we believe it may be possible to develop therapies that restore balance to dysregulated brain circuits and improve long‐term outcomes for patients. image

Astrocytes in the nucleus accumbens (NAC) core have been observed to undergo phenotypic changes associated with drug-seeking behaviour in both humans and animals. However, the role of NAC core astrocytes in non-drug-related instrumental behaviour remains poorly understood. To address this, we chemogenetically activated hM4Di receptors selectively expressed on NAC core astrocytes in rats during food-motivated decision-making tasks. In Experiment 1, rats were first trained to associate two auditory stimuli with two distinct food outcomes (pellets and sucrose), then to press left and right levers for those same outcomes. All training was conducted drug-free, and rats then received intraperitoneal (i.p) injections of either vehicle or deschloroclozapine (DCZ) prior to test. Disrupting astrocytic signalling via DCZ injections left instrumental choice intact when it was guided by cues signalling the sensory-specific properties of each outcome, as tested in specific Pavlovian instrumental transfer and outcome-selective reinstatement, but suppressed responding in an outcome devaluation test. In Experiment 2, a single stimulus and single lever were separately paired with distinct food outcomes, then presented together on test. Control animals demonstrated a general PIT effect, elevating responding during stimulus presentations, and this was prevented by Gi activation on NAC core astrocytes. Immunohistochemistry revealed increased neuronal activity following hM4Di activation in astrocytes. Together, these findings suggest that intact signalling in NAC core astrocytes is necessary for instrumental actions that depend on general arousal or affective processes, but not for actions guided by sensory-specific outcome expectations. Significance Statement: Astrocyte dysfunction in the nucleus accumbens (NAC) has been implicated in several forms of compulsion in humans, yet preclinical work has focussed almost exclusively on drug-taking and seeking. The role of NAC core astrocytes on responding for non-drug outcomes is therefore unclear. Here, using food outcomes, we show that disrupting astrocytic Gi signalling in NAC core selectively impairs actions driven by general motivational states but spares those guided by specific outcome expectations. These findings suggest that NAC core astrocytes play a critical role in invigorating behaviour, extending their involvement beyond drug-seeking in animals and highlighting their potential relevance to compulsive behaviour more generally.