Biology subjects

Skara, V.

Publications and source records attributed to Skara, V..

4 recordsLinked to original sources

bioRxiv2024

A striosomal accumbens pathway drives compulsive seeking behaviors through an aversive Esr1+ hypothalamic-habenula circuit.

The lateral hypothalamic area (LHA) integrates external stimuli with internal states to drive the choice between competing innate or value-driven motivated behaviors. Projections from the LHA to the lateral habenula (LHb) shape internal states, with excitatory estrogen receptor 1-expressing (Esr1+) LHA-LHb neurons driving aversive responses and sustained negative states. Here, we identify and functionally characterize a specific projection from the nucleus accumbens (ACB) that targets Esr1+ LHA-LHb neurons. Using cell-type-specific tracing of monosynaptic inputs, single-nucleus RNA sequencing, and neuroanatomical mapping, we demonstrate that the Esr1+ LHA-LHb pathway receives a major input from a striosomal Tac1+/Tshz1+/Oprm1+ ACB neuron subtype. Intersectional cell-type-specific and input-output defined optogenetic manipulation of this ACB-LHA-LHb pathway revealed its role in signaling aversion after repeated activation, with the negative behavioral state being dependent on recruitment of Esr1+ LHA-LHb neurons. Importantly, we found that activation of the D1+ ACB-LHA pathway drives reward-independent compulsive-like seeking behaviors, expressed as compulsive digging or poking behaviors. We found that these complex yet stereotyped behaviors compete with highly motivated states and can override the need for natural rewards or social stimuli. Our findings reveal a discrete striosomal Tac1+ ACB projection targeting the aversive Esr1+ LHA-LHb pathway as a key circuit that promotes compulsive seeking behaviors over goal-directed actions.

neuroscience↗

bioRxiv2024

Striosomes Target Nigral Dopamine-Containing Neurons via Direct-D1 and Indirect-D2 Pathways Paralleling Classic Direct-Indirect Basal Ganglia Systems

Balanced activity of canonical direct D1 and indirect D2 basal ganglia pathways is considered a core requirement for normal movement, and their imbalance is an etiologic factor in movement and neuropsychiatric disorders. We present evidence for a conceptually equivalent pair of direct-D1 and indirect-D2 pathways that arise from striatal projection neurons (SPNs) of the striosome compartment rather than from SPNs of the matrix, as do the canonical pathways. These S-D1 and S-D2 striosomal pathways target substantia nigra dopamine-containing neurons instead of basal ganglia motor output nuclei. They modulate movement oppositely to the modulation by the canonical pathways: S-D1 is inhibitory and S-D2 is excitatory. The S-D1 and S-D2 circuits likely influence motivation for learning and action, complementing and reorienting canonical pathway modulation. A major conceptual reformulation of the classic direct-indirect pathway model of basal ganglia function is needed, as well as reconsideration of the effects of D2-targeting therapeutic drugs. HIGHLIGHTSO_LIDirect S-D1 and Indirect S-D2 striosomal pathways target SNpc dopamine cells C_LIO_LIThe S-D2 indirect pathway targets a distinct central external pallidal zone (cGPe) C_LIO_LIStimulation of S-D2 increases, of S-D1 decreases, striatal dopamine and movement C_LIO_LIS-D1 SPNs activity brackets task, inverse to a mid-task peak of dopamine release C_LI

neuroscience↗

bioRxiv2022

Sst+ GPi output neurons provide direct feedback to key nodes of the basal ganglia and drive behavioral flexibility.

The internal globus pallidus (GPi) is a basal ganglia output nucleus with separate projections to the thalamus and the lateral habenula (LHb). Here, we show a GPi subtype with projections to LHb (GPi-LHb), genetically defined based on glutamate/GABA co-transmission and somatostatin (Sst) expression, also projects back to key nodes in the basal ganglia: the external globus pallidus (GPe), the striatal striosomes, and dopamine neurons in the substantia nigra. We found that the Sst+ GPi population showed strong movement and direction-specific selectivity in a goal-directed choice task, but not during self-paced exploration, and did not signal prediction errors or outcome modulation. During goal-directed behavior, the Sst+ GPi activity slowly evolved with learning of correct choice actions and genetic silencing disrupted the ability to update choice behavior following a task rule reversal. In summary, we have found that Sst+ GPi neurons establish a wide feedback network in the basal ganglia and drive behavioral flexibility.

neuroscience↗

bioRxiv2022

PRC2-mediated repression is essential to maintain identity and function of differentiated dopaminergic and serotonergic neurons

How neurons in the CNS can maintain cellular identity over an entire lifespan remains largely unknown. Here we show that long-term maintenance of identity in differentiated dopaminergic and serotonergic neurons is critically reliant on the Polycomb repressive complex 2 (PRC2). Deletion of the obligate PRC2-component, Eed, in these neurons, resulted in global loss of H3K27me3, followed by a gradual activation of genes harbouring both H3K27me3 and H3K9me3 modifications. Notably, H3K9me3 was also lost at these PRC2-targets prior to gene activation. Neuronal survival was not compromised, instead there was a reduction in subtype specific gene expression as well as a progressive impairment of dopaminergic or serotonergic neuronal function leading to behavioural deficits characteristic of Parkinsons disease (PD) or mood disorders, respectively. Single cell analysis revealed an unexpected subtype specific vulnerability to loss of PRC2-repression in dopamine neurons of the substantia nigra, the neurons primarily affected in PD. Taken together, our study reveals that a PRC2-dependent non-permissive chromatin state is essential to maintain subtype identity and function of dopaminergic and serotonergic neurons.

neuroscience↗