Biology subjects

Liss, B.

Publications and source records attributed to Liss, B..

6 recordsLinked to original sources

bioRxiv2024

Excitatory neurons of the anterior cingulate cortex encode chosen actions and their outcomes rather than cognitive state

The anterior cingulate cortex (ACC) causally influences cognitive control of goal-directed behaviour. However, it is unclear whether ACC directly encodes cognitive variables like attention or impulsivity, or implements goal-directed action selection mechanisms that are modulated by them. We recorded ACC activity with miniature endoscopic microscopes in mice performing the 5-choice-serial-reaction time task, and applied decoding and encoding analyses. ACC pyramidal cells represented specific actions before and during the behavioural response, whereas the response type (e.g. correct/incorrect/premature) - indicating the state of attentional and impulse control - could only be decoded during and after the response with high reliability. Devaluation and extinction experiments further revealed that action encoding depended on reward expectation. Our findings support a role for ACC in goal-directed action selection and monitoring, that is modulated by cognitive state, rather than in tracking levels of attention or impulsivity directly in individual trials.

neuroscience↗

bioRxiv2022

Deep learning based image analysis identifies a DAT-negative subpopulation of dopaminergic neurons in the lateral Substantia nigra.

Here we present a deep learning-based image analysis platform (DLAP), tailored to autonomously quantify cell numbers, and fluorescence signals within cellular compartments, derived from RNAscope or immunohistochemistry. We utilized DLAP to analyse subtypes of tyrosine hydroxylase (TH)-positive dopaminergic midbrain neurons in mouse and human brain sections. These neurons modulate complex behaviour, and are differentially affected in Parkinsons and other diseases. DLAP allows the analysis of large cell numbers, and facilitates the identification of small cellular subpopulations. Specifically, we identified a small subpopulation of TH-positive neurons ([~]5%), mainly located in the very lateral Substantia nigra (SN), that was immunofluorescence-negative for the plasmalemma dopamine transporter (DAT), with [~]40% smaller cell bodies. These neurons were negative for aldehyde dehydrogenase 1A1, with a lower co-expression rate for dopamine-D2-autoreceptors, but a [~]7-fold higher likelihood of calbindin-d28k co-expression ([~]70%). Our results have important implications, as DAT is crucial for dopamine-signalling, and is commonly used as a marker for dopaminergic SN neurons.

neuroscience↗

bioRxiv2021

Nucleolar stress controls mutant Huntingtin toxicity and monitors Huntington disease progression

Transcriptional and cellular stress surveillance deficits are hallmarks of Huntingtons disease (HD), a fatal autosomal dominant neurodegenerative disorder, caused by a pathological expansion of CAG repeats in the Huntingtin (HTT) gene. The nucleolus, a dynamic nuclear biomolecular condensate and the site of ribosomal RNA (rRNA) transcription, is implicated in the cellular stress response and in protein quality control. While the exact pathomechanisms of HD remain unclear, the impact of nucleolar dysfunction on HD pathophysiology in vivo is elusive. Here we identified aberrant maturation of rRNA and decreased translational rate in association with human mutant Huntingtin (mHTT) expression. Genetic disruption of nucleolar integrity in vulnerable striatal neurons of the R6/2 HD mouse model decreases mHTT disperse state in the nucleus, exacerbating the motor deficits. The protein nucleophosmin 1 (NPM1), important for nucleolar integrity and rRNA maturation, loses its nucleolar localization. NPM1 de-localization occurs in the striatum and in the skeletal muscle of the progressive zQ175 knock-in HD mouse model, mimicking the phenotype of HD patients in skeletal muscle biopsies. Taken together, we showed that nucleolar integrity regulates the formation of mHTT inclusions in vivo, and identified NPM1 as a novel, readily detectable peripheral histopathological marker of HD progression.

neuroscience↗

bioRxiv2021

Highly task-specific and distributed neural connectivity in working memory revealed by single-trial decoding in mice and humans

Working memory (WM), the capacity to briefly and intentionally maintain mental items, is key to successful goal-directed behaviour and impaired in a range of psychiatric disorders. To date, several brain regions, connections, and types of neural activity have been correlatively associated with WM performance. However, no unifying framework to integrate these findings exits, as the degree of their species- and task-specificity remains unclear. Here, we investigate WM correlates in three task paradigms each in mice and humans, with simultaneous multi-site electrophysiological recordings. We developed a machine learning-based approach to decode WM-mediated choices in individual trials across subjects from hundreds of electrophysiological measures of neural connectivity with up to 90% prediction accuracy. Relying on predictive power as indicator of correlates of psychological functions, we unveiled a large number of task phase-specific WM-related connectivity from analysis of predictor weights in an unbiased manner. Only a few common connectivity patterns emerged across tasks. In rodents, these were thalamus-prefrontal cortex delta- and beta-frequency connectivity during memory encoding and maintenance, respectively, and hippocampal-prefrontal delta- and theta-range coupling during retrieval, in rodents. In humans, task-independent WM correlates were exclusively in the gamma-band. Mostly, however, the predictive activity patterns were unexpectedly specific to each task and always widely distributed across brain regions. Our results suggest that individual tasks cannot be used to uncover generic physiological correlates of the psychological construct termed WM and call for a new conceptualization of this cognitive domain in translational psychiatry.

neuroscience↗

bioRxiv2021

Alternative splicing of auxiliary β2-subunits stabilizes Cav2.3 Ca2+ channel activity in continuously active midbrain dopamine neurons

In dopaminergic (DA) substantia nigra (SN) neurons Cav2.3 R-type Ca2+-currents contribute to somatodendritic Ca2+-oscillations. These may contribute to the selective degeneration of these neurons in Parkinsons disease (PD) since Cav2.3-knockout is neuroprotective in a PD mouse model. However, the typical Cav2.3 gating would predict complete channel inactivation during SN DA neuronal firing. Here we show that in tsA-201-cells the membrane-anchored {beta}2-splice variants {beta}2a and {beta}2e stabilize Cav2.3 gating properties allowing sustained Cav2.3 availability during simulated pacemaking and enhanced Ca2+-currents during bursts. We confirmed the expression of {beta}2a and {beta}2e-subunits in the SN and identified SN DA neurons. Patch-clamp recordings of SN DA neurons in mouse brain slices revealed R-type Ca2+-currents similar to {beta}2a- or {beta}2e-stabilized Cav2.3-currents and recordings in cultured murine DA neurons confirmed their activity during pacemaking. Taken together, our data support an important (patho)physiological role of {beta}-subunit alternative splicing for Cav2.3 Ca2+-signaling in highly vulnerable SN DA neurons.

neuroscience↗

bioRxiv2018

Schizophrenia-related cognitive dysfunction in the Cyclin-D2 knockout mouse model of ventral hippocampal hyperactivity

Elevated activity at the output stage of the anterior hippocampus has been described as a physiological endophenotype of schizophrenia, and its development maps onto the transition from its prodromal to its psychotic state. Interventions that halt the spreading glutamatergic over-activity in this region and thereby the development of overt schizophrenia could be promising therapies. However, animal models with high construct validity to support such pre-clinical development are scarce. The Cyclin-D2 knockout (CD2-KO) mouse model shows a hippocampal Parvalbumin-interneuron dysfunction and its pattern of hippocampal over-activity shares similarities with that seen in prodromal patients. In a comprehensive phenotyping of CD2-KO mice, we found that they displayed novelty-induced hyperlocomotion (a correlate in the positive symptom domain), that was largely resistant against D1- and D2-dopamine receptor antagonism, but responsive to the mGluR2/3-agonist LY379268. In the negative symptom domain, CD2-KO mice showed transiently reduced sucrose-preference (anhedonia), but enhanced interaction with novel mice and objects, as well as normal nest building and incentive motivation. Also, unconditioned anxiety, perseveration, and motor impulsivity were unaltered. However, in the cognitive domain, CD2-knockouts showed reduced executive function in assays of rule-shift and rule-reversal learning, but also an impairment in working memory, that was resistant against LY379268. In contrast, sustained attention and forms of spatial and object-related memory that are mediated by short-term habituation of stimulus-specific attention were intact. Our results suggest, that CD2-KO mice are a valuable model in translational research targeted at the pharmacoresistant cognitive symptom domain in causal relation to hippocampal over-activity in the prodrome-to-psychosis transition.

animal behavior and cognition↗