nucleus accumbens

Targeting thalamic circuits rescues motor and mood deficits in PD mice

Although bradykinesia, tremor, and rigidity are hallmark motor defects in Parkinson’s disease (PD) patients, they also experience motor learning impairments and non-motor symptoms such as depression. The neural basis for these different PD symptoms are not well understood. While current treatments are effective for locomotion deficits in PD, therapeutic strategies targeting motor learning deficits and non-motor symptoms are lacking. We found that distinct parafascicular (PF) thalamic subpopulations project to caudate putamen (CPu), subthalamic nucleus (STN), and nucleus accumbens (NAc). While PF-->CPu and PF-->STN circuits are critical for locomotion and motor learning respectively, inhibition of the PF-->NAc circuit induced a depression-like state. While chemogenetically manipulating CPu-projecting PF neurons led to a long-term restoration of locomotion, optogenetic long-term potentiation at PF-->STN synapses restored motor learning behavior in PD model mice. Furthermore, activation of NAc-projecting PF neurons rescued depression-like PD phenotypes. Importantly, we identified nicotinic acetylcholine receptors capable of modulating PF circuits to rescue different PD phenotypes. Thus, targeting PF thalamic circuits may be an effective strategy for treating motor and non-motor deficits in PD.

Neuronal sub-populations in the nucleus accumbens represent distinct valence-free parameters to drive behavior

Dissecting the role of accumbal D1 and D2 medium spiny neurons in information encoding

Nearly all motivated behaviors require the ability to associate outcomes with specific actions and make adaptive decisions about future behavior. The nucleus accumbens (NAc) is integrally involved in these processes. The NAc is a heterogeneous population primarily composed of D1 and D2 medium spiny projection (MSN) neurons that are thought to have opposed roles in behavior, with D1 MSNs promoting reward and D2 MSNs promoting aversion. Here we examined what types of information are encoded by the D1 and D2 MSNs using optogenetics, fiber photometry, and cellular resolution calcium imaging. First, we showed that mice responded for optical self-stimulation of both cell types, suggesting D2-MSN activation is not inherently aversive. Next, we recorded population and single cell activity patterns of D1 and D2 MSNs during reinforcement as well as Pavlovian learning paradigms that allow dissociation of stimulus value, outcome, cue learning, and action. We demonstrated that D1 MSNs respond to the presence and intensity of unconditioned stimuli – regardless of value. Conversely, D2 MSNs responded to the prediction of these outcomes during specific cues. Overall, these results provide foundational evidence for the discrete aspects of information that are encoded within the NAc D1 and D2 MSN populations. These results will significantly enhance our understanding of the involvement of the NAc MSNs in learning and memory as well as how these neurons contribute to the development and maintenance of substance use disorders.

Stress deceleration theory: chronic adolescent stress exposure results in decelerated neurobehavioral maturation

Normative development in adolescence indicates that the prefrontal cortex is still under development thereby unable to exert efficient top-down inhibitory control on subcortical regions such as the basolateral amygdala and the nucleus accumbens. This imbalance in the developmental trajectory between cortical and subcortical regions is implicated in expression of the prototypical impulsive, compulsive, reward seeking and risk-taking adolescent behavior. Here we demonstrate that a chronic mild unpredictable stress procedure during adolescence in male Wistar rats arrests the normal behavioral maturation such that they continue to express adolescent-like impulsive, hyperactive, and compulsive behaviors into late adulthood. This arrest in behavioral maturation is associated with the hypoexcitability of prelimbic cortex (PLC) pyramidal neurons and reduced PLC-mediated synaptic glutamatergic control of BLA and nucleus accumbens core (NAcC) neurons that lasts late into adulthood. At the same time stress exposure in adolescence results in the hyperexcitability of the BLA pyramidal neurons sending stronger glutamatergic projections to the NAcC. Chemogenetic reversal of the PLC hypoexcitability decreased compulsivity and improved the expression of goal-directed behavior in rats exposed to stress during adolescence, suggesting a causal role for PLC hypoexcitability in this stress-induced arrested behavioral development. (https://www.biorxiv.org/content/10.1101/2021.11.21.469381v1.abstract)

Dopaminergic modulation of synaptic plasticity in learning and psychiatric disorders

Transient changes in dopamine activity in response to reward and punishment have been known to regulate reward-related learning. However, the cellular basis that detects the transient dopamine signaling has long been unclear. Using two-photon microscopy and optogenetics, I have shown that transient increases and decreases of dopamine modulate plasticity of dopamine D1 and D2 receptor-expressing cells in the nucleus accumbens, respectively. At the behavioral level, I characterized that these D1 and D2 cells cooperatively tune learning by generalization and discrimination learning. Interestingly, disturbance of the dopamine signaling impaired D2 cell plasticity and discrimination learning, which was analogous to salience misattribution seen in subjects with schizophrenia.

Dopamine release in the nucleus accumbens core signals perceived saliency

Anterior Cingulate inputs to nucleus accumbens control the social transfer of pain and analgesia

Empathy plays a critical role in social interactions, and many species, including rodents, display evolutionarily conserved behavioral antecedents of empathy. In both humans and rodents, the anterior cingulate cortex (ACC) encodes information about the affective state of others. However, little is known about which downstream targets of the ACC contribute to empathy behaviors. We optimized a protocol for the social transfer of pain behavior in mice and compared the ACC-dependent neural circuitry responsible for this behavior with the neural circuitry required for the social transfer of two related states: analgesia and fear. We found that a 1-hour social interaction between a bystander mouse and a cagemate experiencing inflammatory pain led to congruent mechanical hyperalgesia in the bystander. This social transfer led to activation of neurons in the ACC and several downstream targets, including the nucleus accumbens (NAc), which was revealed by monosynaptic rabies virus tracing to be directly connected to the ACC. Bidirectional manipulation of activity in ACC-to-NAc inputs influenced the acquisition of socially transferred pain. Further, the social transfer of analgesia also depended upon ACC-NAc inputs. By contrast, the social transfer of fear instead required activity in ACC projections to the basolateral amygdala. This shows that mice rapidly adopt the sensory-affective state of a social partner, regardless of the valance of the information (pain, fear, or pain relief). We find that the ACC generates specific and appropriate empathic behavioral responses through distinct downstream targets. More sophisticated understanding of evolutionarily conserved brain mechanisms of empathy will also expedite the development of new therapies for the empathy-related deficits associated with a broad range of neuropsychiatric disorders.

Nr4a1-mediated morphological adaptations in Ventral Pallidal projections to Mediodorsal Thalamus support cocaine intake and relapse-like behaviors

Growing evidence suggests the ventral pallidum (VP) is critical for drug intake and seeking behaviors. Receiving dense projections from the nucleus accumbens as well as dopamine inputs from the midbrain, the VP plays a central role in the control of motivated behaviors. Repeated exposure to cocaine is known to alter VP neuronal firing and neurotransmission. Surprisingly, there is limited information on the molecular adaptations occurring in VP neurons following cocaine intake.To provide insights into cocaine-induced transcriptional alterations we performed RNA-sequencing on VP of mice following cocaine self-administration. Gene Ontology analysis pointed toward alterations in dendrite- and spinerelated genes. Subsequent transcriptional regulator analysis identified the transcription factor Nr4a1 as a common regulator for these sets of morphology-related genes.Consistent with the central role of the VP in reward, its neurons project to several key regions associated with cocaine-mediated behaviors. We thus assessed Nr4a1 expression levels in various projection populations.Following cocaine self-administration, VP neurons projecting to the mediodorsal thalamus (MDT) showed significantly increased Nr4a1 levels. To further investigate the role of Nr4a1 in cocaine intake and relapse, we bidirectionally manipulated its expression levels selectively in VP neurons projecting to the MDT. Increasing Nr4a1 levels resulted in enhanced relapse-like behaviors accompanied by a blockage of cocaine-induced spinogenesis.However, decreasing Nr4a1expression levels completely abolished cocaine intake and consequential relapse-like behaviors. Together, our preliminary findings suggest that drug-induced neuronal remodeling in pallido-thalamic circuits is critical for cocaine intake and relapse-like behaviors.

Striatal circuits for reward learning and decision-making

How are actions linked with subsequent outcomes to guide choices? The nucleus accumbens (NAc), which is implicated in this process, receives glutamatergic inputs from the prelimbic cortex (PL) and midline regions of the thalamus (mTH). However, little is known about what is represented in PL or mTH neurons that project to NAc (PL-NAc and mTH-NAc). By comparing these inputs during a reinforcement learning task in mice, we discovered that i) PL-NAc preferentially represents actions and choices, ii) mTH-NAc preferentially represents cues, iii) choice-selective activity in PL-NAc is organized in sequences that persist beyond the outcome. Through computational modelling, we demonstrate that these sequences can support the neural implementation of temporal difference learning, a powerful algorithm to connect actions and outcomes across time. Finally, we test and confirm predictions of our circuit model by direct manipulation of PL-NAc neurons. Thus, we integrate experiment and modelling to suggest a neural solution for credit assignment.

KETAMINE ATTENUATES CONTEXT-INDUCED REINSTATEMENT OF ETHANOL SEEKING AND NUCLEUS ACCUMBENS ACTIVATION IN MICE

FENS Forum 2026

BEHAVIOURAL RIGIDITY AS A TRANSDIAGNOSTIC MARKER OF NUCLEUS ACCUMBENS ALTERATIONS IN DEMENTIA

FENS Forum 2026

EFFECTS OF AN OBESOGENIC DIET ON EXCITATORY SYNAPTIC PLASTICITY IN THE NUCLEUS ACCUMBENS

FENS Forum 2026

NUCLEUS ACCUMBENS CONTROL OF VTA MODULATION OF HIPPOCAMPAL MEMORY CONSOLIDATION

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THE NUCLEUS ACCUMBENS SHELL REGULATES HEDONIC FEEDING VIA A ROSTRAL HOTSPOT

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BIDIRECTIONAL NUCLEUS ACCUMBENS-MIDBRAIN CIRCUITS AND THEIR INVOLVEMENT IN ADAPTIVE REWARD PROCESSING

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INVOLVEMENT OF THE VENTRAL TEGMENTAL AREA – NUCLEUS ACCUMBENS AND VENTRAL TEGMENTAL AREA – BASOLATERAL AMYGDALA CIRCUITS IN THE REINFORCING EFFECTS OF NICOTINE

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INVESTIGATING THE BRAIN CRF AND OXT SYSTEMS IN THE NUCLEUS ACCUMBENS: IMPLICATIONS FOR POOR MOTHERING IN LACTATING RATS

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ADOLESCENT ALCOHOL ABUSE ARRESTS ELECTROPHYSIOLOGICAL PHENOTYPE OF NUCLEUS ACCUMBENS MEDIUM SPINY NEURONS IN A LATE DEVELOPMENTAL STATE

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MOLECULAR AND ANATOMICAL DIVERSITY OF NUCLEUS ACCUMBENS NEURONS UNDERLYING MALADAPTIVE REWARD PROCESSING

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IMPACT OF AGE ON EFFORT MOTIVATED BEHAVIOR AND ON THE CEREBRAL DOPAMINE NEUROTROPHIC FACTOR (CDNF) IN THE NUCLEUS ACCUMBENS

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AN ASTROCYTE ENSEMBLE MODULATES SYNAPTIC COMMUNICATION IN THE MEDIAL PREFRONTAL CORTEX-NUCLEUS ACCUMBENS CIRCUIT

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FROM FEAR TO ACTION: BASOLATERAL AMYGDALA–NUCLEUS ACCUMBENS CIRCUIT MECHANISMS IN AVOIDANCE LEARNING

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NUCLEUS ACCUMBENS DOPAMINE SIGNALLING THAT LINKS PREDICTIVE CODING AND MOTIVATIONAL SALIENCE THROUGH THE ENCODING OF STATISTICAL DEVIANCE

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TESTOSTERONE REMODELS ASTROCYTE ENDFEET IN THE NUCLEUS ACCUMBENS TO MODULATE ANXIETY BEHAVIOUR

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MANIPULATION OF DOPAMINERGIC ACTIVITY IN THE NUCLEUS ACCUMBENS CORE PRODUCES DOSE-DEPENDENT CHANGES IN FUNCTIONAL AND DYSFUNCTIONAL CHECKING BEHAVIOUR ON THE OBSERVING RESPONSE TASK

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RESPONSE OF CDNF IN NUCLEUS ACCUMBENS CORE IN MICE OF BOTH SEXES: CELLULAR AND NEUROANATOMICAL LOCALIZATION

FENS Forum 2026

PARAVENTRICULAR THALAMUS INPUTS TO THE NUCLEUS ACCUMBENS MODULATE DOPAMINE SIGNALING AND OPIOID RESPONSES IN CHRONIC PAIN

FENS Forum 2026

CCK- AND CCK+ BASAL AMYGDALA-NUCLEUS ACCUMBENS GLUTAMATE PRINCIPAL NEURONS: COMPARISON OF THEIR CIRCUITS AND INVOLVEMENT IN REWARD AND AVERSION PROCESSING

FENS Forum 2026

REDUCED EXPRESSION OF METABOTROPIC GLYCINE RECEPTOR IN THE NUCLEUS ACCUMBENS CONTRIBUTES TO SYNAPTIC DYSFUNCTION IN STRESS-SUSCEPTIBLE MICE

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CENTRAL KISSPEPTIN-8 INHIBITS SPONTANEOUS LOCOMOTION VIA NEUROCHEMICAL MODULATION OF THE VENTRAL TEGMENTAL AREA – NUCLEUS ACCUMBENS CIRCUIT IN RATS

FENS Forum 2026

MODULATION OF D1 DOPAMINE RECEPTORS IN THE NUCLEUS ACCUMBENS AFFECTS PARENTAL AND INFANTICIDAL BEHAVIOR IN FEMALE AND MALE (C57BL6) MICE

FENS Forum 2026

A BRAIN-WIDE ATLAS OF ASTROCYTIC OXYTOCIN RECEPTORS IN MOUSE AND RAT REVEALS A GLIAL BASIS FOR NUCLEUS ACCUMBENS MODULATION OF PRO-SOCIAL BEHAVIOR

FENS Forum 2026

GPR55 ACTIVATION MODULATES GLIAL REACTIVITY AND DOPAMINERGIC SIGNALING IN THE NUCLEUS ACCUMBENS DURING COCAINE-INDUCED LOCOMOTOR SENSITIZATION

FENS Forum 2026

ACUTE CORTICOSTERONE ADMINISTRATION INDUCES DEPRESSION-LIKE BEHAVIORS THROUGH DOPAMINE DEPLETION IN THE NUCLEUS ACCUMBENS

FENS Forum 2026

ENERGY-DEPENDENT MODULATION OF NUCLEUS ACCUMBENS OUTPUT VIA K-ATP CHANNEL ACTIVITY

FENS Forum 2026

CHRONIC INFLAMMATORY PAIN ALTERS REWARD-EVOKED DOPAMINE DYNAMICS IN THE NUCLEUS ACCUMBENS

FENS Forum 2026

Molecular, cellular and behavioral characterization of glycine receptors in the nucleus accumbens in the APP/PS1 mice

Molecular candidates in the nucleus accumbens shell involved in the protective effect of social interaction when available as an alternative to cocaine

Chronic exposure to high fat diet affects the dopamine modulation in nucleus accumbens of adolescent male rats: Implications in hedonic food intake

MeCP2 controls drug addiction differently depending on cell type in the nucleus accumbens

Lesions of Nucleus Accumbens Shell abolish Socially Transmitted Food Preferences

Capturing, tracking, and profiling cocaine-recruited neuronal ensembles in the nucleus accumbens

Kisspeptin-8 suppresses locomotion and modulates nucleus accumbens activity in rats

K-ATP channels link mitochondrial (dys)function to neuronal excitability in the nucleus accumbens

Brain stress and noradrenergic system mediate the mechanisms underlying relapse caused by exposure to Social Defeat in the nucleus accumbens in morphine dependent mice

Involvement of nucleus accumbens parvalbumin interneurons in cocaine seeking behavior

Implication of medial prefrontal cortex and nucleus accumbens dopamine transmission in goal-directed behaviors: a role for dopamine and NMDA receptors heteromers ?

Blood brain barrier differences in the nucleus accumbens relate to natural variation in trait anxiety

Dopamine release in the nucleus accumbens during backward conditioning

COSYNE 2023