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.

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

Decoding cocaine-induced proteomic adaptations in the mouse nucleus accumbens

FENS Forum 2024

The neurometabolic underpinnings of social rank – underlying mechanisms in the astrocytes of the nucleus accumbens

FENS Forum 2024

Probing neural value computations in the nucleus accumbens dopamine signal

COSYNE 2022

Probing neural value computations in the nucleus accumbens dopamine signal

COSYNE 2022

Role of the prefrontal cortex and nucleus accumbens in maternal and infanticidal behavior in naïve mice (C57BL6)

FENS Forum 2024

Dopamine release in the nucleus accumbens during backward conditioning

COSYNE 2023

Activating Neuronal Ensembles in the Nucleus Accumbens Enhances Cocaine-Conditioned Place Preference

Astrocytes of Nucleus Accumbens Control the Impairments Derived from Chronic Exposure of THC

Basal amygdala-nucleus accumbens glutamate neurons are important for reward behaviour and both are dysregulated by chronic social stress in mice

The basolateral amygdala to nucleus accumbens shell pathway encodes, but doesn’t retrieve, outcome-specific predictions to guide choice between actions

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

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

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

Communication Between the Hippocampus, Nucleus Accumbens and Ventral Tegmental Area During Learning and Memroy

Sex differences in neural representation of threat in ventral hippocampal and prefrontal cortical projections to nucleus accumbens

Divergent role of nucleus accumbens D2-MSN-ventral pallidum projections in different phases of motivated behavior

The Effect of Social Isolation on Cancer Metastases and the Nucleus Accumbens in Rats

Glutamatergic afferents to the nucleus accumbens integrate outcomes in reward-learning

High fat diet feeding disrupts nucleus accumbens core regulated motivational control over food-seeking behaviour

Hybridization-based in situ sequencing in the nucleus accumbens reveals peripubertal stress-induced changes in several cell types

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

Involvement of nucleus accumbens parvalbumin interneurons in cocaine seeking behavior

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

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

Lesions of Nucleus Accumbens Shell abolish Socially Transmitted Food Preferences

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

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

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

Novel Ca2+-modulated Photoactivatable Imaging Reveals Neuron-Astrocyte Glutamatergic Circuitries within the Nucleus Accumbens

A novel endocannabinoid hydrolase FAAH inhibitor as a potential antidepressant induces gene expression changes in nucleus accumbens in a BALB/c mice acute stress model

Prenatal glucocorticoid exposure alters effort decision making and triggers nucleus accumbens and anterior cingulate cortex functional changes

Pharmacological activation of histamine receptor type 2 enhances evoked firing in medium spiny neurons of the nucleus accumbens through downregulation of Kv4.2 channels

Role of CYFIP2 on medial prefrontal cortex to nucleus accumbens pathway in regulation of cocaine reward

The role of Microglia in synaptic adaptations in the nucleus accumbens after cocaine-induced conditioned place preference

The role of the nucleus accumbens shell in alcohol use despite negative consequences

Spatial and reward coding of dorsal hippocampus projection neurons to the nucleus accumbens

TRPA1 can modulate cocaine addiction within glutamatergic neurons extending from medial frontal cortex to nucleus accumbens

Characterization of the cerebral dopamine neurotrophic factor (CDNF) in nucleus accumbens of rodents

FENS Forum 2024

LDT cholinergic inputs to the nucleus accumbens neurons facilitate cocaine reinforcing properties

FENS Forum 2024