Biology subjects

Chancey, J. H.

Publications and source records attributed to Chancey, J. H..

2 recordsLinked to original sources

bioRxiv2023

Dopaminergic D2 receptor modulation of striatal cholinergic interneurons governs sequence learning

Learning action sequences is necessary for normal daily activities. Medium spiny neurons (MSNs) in the dorsal striatum (dStr) encode action sequences through changes in firing at the start and/or stop of action sequences or sustained changes in firing throughout the sequence. Acetylcholine (ACh), released from cholinergic interneurons (ChIs), regulates striatal function by modulating MSN and interneuron excitability, dopamine and glutamate release, and synaptic plasticity. Cholinergic neurons in dStr pause their tonic firing during the performance of learned action sequences. Activation of dopamine type-2 receptors (D2Rs) on ChIs is one mechanism of ChI pausing. In this study we show that deleting D2Rs from ChIs by crossing D2-floxed with ChAT-Cre mice (D2Flox-ChATCre), which inhibits dopamine-mediated ChI pausing and leads to deficits in an operant action sequence task and lower breakpoints in a progressive ratio task. These data suggest that D2Flox-ChATCre mice have reduced motivation to work for sucrose reward, but show no generalized motor skill deficits. D2Flox-ChATCre mice perform similarly to controls in a simple reversal learning task, indicating normal behavioral flexibility, a cognitive function associated with ChIs. In vivo electrophysiological recordings show that D2Flox-ChatCre mice have deficits in sequence encoding, with fewer dStr MSNs encoding entire action sequences compared to controls. Thus, ChI D2R deletion appears to impair a neural substrate of action chunking. Virally replacing D2Rs in dStr ChIs in adult mice improves action sequence learning, but not the lower breakpoints, further suggesting that D2Rs on ChIs in the dStr are critical for sequence learning, but not for driving the motivational aspects of the task. Significance statementThe role of striatal projection neurons in encoding action sequences has been extensively studied, and cholinergic interneurons play a central role in striatal physiology, but we do not yet understand how cholinergic interneurons contribute to action sequencing. Using a combination of mouse genetics, behavior, and in vivo electrophysiology this work shows that genetic deletion of D2 receptors from striatal cholinergic interneurons disrupts the learning, performance, and encoding of action sequences, without changing general locomotion or motor skill learning. Virally replacing D2 receptors specifically in dorsal striatal cholinergic interneurons is sufficient to rescue the sequence behavior. Our observations may be useful in understanding and treating movement disorders in which dopamine and acetylcholine are imbalanced.

neuroscience↗

bioRxiv2023

Complex synaptic and intrinsic interactions disrupt input/output functions in the hippocampus of Scn1b knockout mice

Mutations in the SCN1B gene have been linked to severe developmental epileptic encephalopathies including Dravet syndrome. Scn1b knockout (KO) mice model SCN1B loss of function disorders, demonstrating seizures, developmental delays, and early death.SCN1B encodes the protein {beta}1, an ion channel auxiliary subunit that also has roles in cell adhesion, neurite outgrowth, and gene expression. The goal of this project is to better understand of how loss of {beta}1 alters information processing in the brain, resulting in seizures and associated cognitive dysfunction. Using slice electrophysiology in the CA1 region of the hippocampus from male and female Scn1b KO mice and wild-type (WT) littermates, we found that processing of physiologically relevant patterned Schaffer collateral (SC) stimulation produces larger, prolonged depolarizations and increased spiking in KO neurons compared to WTs. KO neurons exhibit enhanced intrinsic excitability, firing more action potentials with current injection. Interestingly, SC stimulation produces smaller, more facilitating excitatory and inhibitory postsynaptic currents in KO pyramidal neurons, but larger postsynaptic potentials with the same stimulation. We also found reduced intrinsic firing of parvalbumin-expressing interneurons and disrupted recruitment of both parvalbumin- and somatostatin-expressing interneurons in response to patterned synaptic stimulation. Neuronal information processing relies on the interplay between synaptic properties, intrinsic properties that amplify or suppress incoming synaptic signals, and firing properties that produce cellular output. We found changes at each of these levels in Scn1b KO pyramidal neurons, resulting in fundamentally altered information processing in the hippocampus that likely contributes to the complex phenotypes of SCN1B-linked epileptic encephalopathies. Significance statementGenetic developmental epileptic encephalopathies have limited treatment options, in part due to our lack of understanding of how genetic changes result in dysfunction at the cellular and circuit levels. SCN1B is a gene linked to Dravet syndrome and other epileptic encephalopathies, and Scn1b knockout mice phenocopy the human disease, allowing us to study underlying neurophysiological changes. Here we found changes at all levels of neuronal information processing in brains lacking {beta}1, including intrinsic excitability, synaptic properties, and synaptic integration, resulting in greatly enhanced input/output functions of the hippocampus. Our study shows that loss of {beta}1 results in a complex array of cellular and network changes that fundamentally alters information processing in the hippocampus.

neuroscience↗