Biology subjects

Carter, A. G.

Publications and source records attributed to Carter, A. G..

5 recordsLinked to original sources

bioRxiv2026

Differential cortical and thalamic engagement of cholinergic interneurons in the nucleus accumbens core

Cholinergic interneurons (CINs) in the nucleus accumbens (NAc) play a key role in regulating motivated behaviors. Here we examine the connectivity and functional impact of cortical and thalamic inputs onto CINs in the NAc core. We first use cell-type specific retrograde anatomy to identify the prefrontal cortex and thalamus as putative afferents. We then combine ex vivo slice physiology and optogenetics to characterize the properties of synapses onto CINs. We demonstrate that thalamic inputs strongly facilitate, whereas cortical inputs exhibit marked depression. We also show that a combination of AMPA and NMDA receptors contribute to both cortical and thalamic responses. Lastly, we establish how these inputs and receptors evoke action potentials and influence spontaneous firing. Our findings show how CINs in the NAc core process long-range inputs, highlighting differences from equivalent circuits in other parts of striatum. SIGNFICANCE STATEMENTCholinergic interneurons provide the primary source of acetylcholine in the striatum and are important for behavior and disease. The types of afferents that drive these interneurons have been examined in dorsal striatum but remain understudied in the nucleus accumbens. We found that inputs from prefrontal cortex and thalamus are the main drivers in the mouse nucleus accumbens core. We compare the sign, dynamics, and impact of these two excitatory inputs, showing how they engage multiple glutamate receptors to influence cholinergic interneuron firing.

neuroscience↗

bioRxiv2026

Substantia nigra pars reticulata regulates prefrontal cortex via ventromedial thalamus

The ventromedial thalamus (VM) innervates layer 1 (L1) of the medial prefrontal cortex (mPFC) to influence executive function and arousal. Thalamocortical (TC) cells in VM process inputs from cortex that are important for generating persistent activity in closed reciprocal loops. However, little is known about connectivity and influence of subcortical inputs to TC cells, and how they are routed through VM to circuits in the mPFC. Here we use anatomical tracing, electrophysiology, and optogenetics to investigate subcortico-thalamo-cortical circuits in mouse VM. We first characterize the morphology and physiology of TC cells in VM and determine their main subcortical input arises from substantia nigra pars reticulata (SNr). We then show how SNr inputs make strong inhibitory connections onto TC cells, which are mediated by GABAA receptors and effectively suppress action potential firing. Lastly, we utilize intersectional approaches to show how SNr inputs are channeled via TC cells in VM to engage specific inhibitory networks in L1 of mPFC. Together, our results indicate how subcortical inputs engage higher-order thalamus to influence the frontal cortex, highlighting differences from equivalent circuits in motor systems. SIGNIFICANCE STATEMENTHere we use anatomy, slice physiology, and optogenetics to examine how subcortical inputs are routed through the ventral medial thalamus (VM) to the medial prefrontal cortex (mPFC). We first find that the main subcortical input to thalamocortical (TC) cells arises from substantia nigra pars reticulata (SNr), rather than cerebellum or internal globus pallidus. We then use electrophysiology and optogenetics to show that SNr input is inhibitory, mediated by GABAA receptors, and sufficient to silence TC cell firing. Lastly, we demonstrate that SNr inputs are channeled via TC cells in VM to engage NDNF+ interneurons in layer 1 (L1) of the mPFC. Together, our findings illustrate how subcortical inputs can signal through higher-order thalamus to influence frontal cortical circuits.

neuroscience↗

bioRxiv2022

Cell type-specific disruption of cortico-striatal circuitry drive repetitive patterns of behaviour in fragile X syndrome model mice

Individuals with fragile X syndrome (FXS) are frequently diagnosed with autism spectrum disorder (ASD), including increased risk for restricted and repetitive behaviours (RRBs). Consistent with observations in humans, FXS model mice display distinct RRBs and hyperactivity that are consistent with dysfunctional cortico-striatal circuits, an area relatively unexplored in FXS. Using a multidisciplinary approach, we dissected the contribution of two populations of striatal medium spiny neurons (SPNs) in the expression of RRBs in FXS model mice. We found that dysregulated protein synthesis at cortico-striatal synapses is a molecular culprit of the synaptic and ASD-associated motor phenotypes displayed by FXS model mice. Cell-type-specific translational profiling of the FXS mouse striatum revealed differentially translated mRNAs, providing critical information concerning potential therapeutic targets. Our findings represent the first evidence of a cell-type specific impact of the loss of FMRP on translation and the sequence of neuronal events in the striatum that drive RRBs in FXS. HighlightsDysregulated striatal protein synthesis underlies altered synaptic plasticity and RRBs displayed by FXS model mice FXS model mice exhibit cell type-specific molecular, morphological, and synaptic changes in the dorsolateral striatum Selective deletion of Fmr1 from dSNPs in mice alters translation and causes repetitive behavior TRAP-Seq indicates that there is altered binding of >120 mRNAs to ribosomes in dSNPs of Fmr1 KO mice G-protein signaling (RGS) 4 translation is significantly reduced in dSPNs in FXS model mice Treatment of FXS model mice with VU0152100, a positive allosteric modulator of the M4 muscarinic receptor that is upstream of RGS4, can reverse RRBs

neuroscience↗

bioRxiv2021

Rostral and caudal BLA engage distinct circuits in the prelimbic and infralimbic PFC

Connections from the basolateral amygdala (BLA) to medial prefrontal cortex (PFC) regulate memory and emotion and become disrupted in neuropsychiatric disorders. We hypothesized that the diverse roles attributed to interactions between the BLA and PFC reflect multiple circuits nested within a wider network. To assess these circuits, we first used anatomy to show that the rostral BLA (rBLA) and caudal BLA (cBLA) differentially project to prelimbic (PL) and infralimbic (IL) subregions of the PFC, respectively. We then combined in vivo silicon probe recordings and optogenetics to show that rBLA primarily engages PL, whereas cBLA mainly influences IL. Using ex vivo whole-cell recordings and optogenetics, we then assessed which neuronal subtypes are targeted, showing that rBLA preferentially drives layer 2 (L2) cortico-amygdalar (CA) neurons in PL, whereas cBLA drives layer 5 (L5) pyramidal tract (PT) cells in IL. Lastly, we used soma-tagged optogenetics to explore the local circuits linking superficial and deep layers of PL, showing how rBLA can also impact L5 PT cells. Together, our findings delineate how subregions of the BLA target distinct networks within the PFC to have different influence on prefrontal output.

neuroscience↗

bioRxiv2020

Mediodorsal and ventromedial thalamus engage distinct L1 circuits in the prefrontal cortex

Interactions between the thalamus and prefrontal cortex (PFC) play a critical role in cognitive function and arousal. Here we use anatomical tracing, electrophysiology, optogenetics, and 2-photon Ca2+ imaging to determine how ventromedial (VM) and mediodorsal (MD) thalamus target specific cell types and subcellular compartments in layer 1 (L1) of mouse PFC. We find thalamic inputs make distinct connections in L1, where VM engages NDNF+ cells in L1a, and MD drives VIP+ cells in L1b. These separate populations of L1 interneurons participate in different disinhibitory networks in superficial layers by targeting either PV+ or SOM+ interneurons. NDNF+ cells also inhibit the apical dendrites of L5 pyramidal tract (PT) cells, where they suppress AP-evoked Ca2+ signals. Lastly, NDNF+ cells mediate a unique form of thalamus-evoked inhibition at PT cells, selectively blocking VM-evoked dendritic Ca2+ spikes. Together, our findings reveal how two thalamic nuclei differentially communicate with the PFC through distinct L1 micro-circuits.

neuroscience↗