Patch-clamp electrophysiology

Experiencing stress during adolescence profoundly alters the neural systems that control goal-directed flexible behaviour. These changes are persistent and are thought to drive behavioural inflexibility in adults, a hallmark symptom of several mental illnesses, including addiction, depression, obsessive compulsive disorder and schizophrenia. The ventral hippocampus (vH) is heavily impacted by stress, however, its role in flexible behaviour remains unclear, partially due to its heterogeneity. Thus, the current study investigates how individual vH projection populations contribute to behavioural

Nociceptors are a subset of sensory neurons that relay painful stimuli from the peripheral tissues. Multiple nociceptor subtypes exist and can respond to different thermal, mechanical, or chemical noxious stimuli. Recent findings with transcriptomics have identified gene expression patterns that classify these sub-types by different ion channels including NaV1.7, NaV1.8, NaV1.9, TRPV1, TRPA1, P2X3, HCN and a number of others that have been implicated in pain. In this study, we have identified a method to rapidly generate a novel TRPA1+ human induced pluripotent stem cell (hiPSC)-derived sensor

Higher-order mental representations underlying working memory function, are believed to arise in primates, with the development and expansion of the granular prefrontal cortex (PFC). For example, in vivo extracellular recordings from behaving non-human primates (NHPs) have shown that persistent firing representing the contents of working memory can be found in lateral PFC but is absent in early sensory areas such as primary visual (V1) cortex. However, the mechanistic basis of potentially unique primate PFC circuitry remains speculative, partly due to the lack of data on the biophysical and m

Gain-of-function variants in the Na+-regulated K+ channel KCNT1 are associated to severe, drug-resistant forms of epilepsy. Quinidine has been used as a KCNT1 blocker, both in vitro and in vivo, though with conflicting clinical outcomes.To identify novel KCNT1 blockers, in the present work an in-house library of >800 compounds underwent a virtual screening based on docking energy scores and similarity to the quinidine bound conformation in a homology model of hKCNT1. Twenty molecules were selected and further screened in vitro using a Tl+-based fluorescent assay in KCNT1-expressing CHO cell

GABAergic inhibitory neurons fundamentally shape the activity and plasticity of cortical circuits. Subset of these neurons contains somatostatin (SOM); these cells play crucial roles in neuroplasticity, learning and memory in many brain areas including the hippocampus, and are implicated in neuropsychiatric diseases and neurodegenerative disorders. Two main types of SOM-containing cells in area CA1 of the hippocampus are oriens-lacunosum-moleculare (OLM) and hippocampo-septal cells. These cell types show many similarities in their soma-dendritic architecture, but they have different axonal tar

Age-related neurodegenerative diseases are becoming more prevalent as human lifespan increases. Modeling human aging is challenging in the lab. We use transdifferentiation via an all-in-one lentiviral vector to directly reprogram human donor-derived fibroblasts into induced neurons (iN). The advantage of this methodology is the maintaining of age and disease-related signatures of the donor cells as iNs bypass the intermediary cell rejuvenation.Huntington’s disease (HD) is an autosomal dominant age-related neurodegenerative disorder caused by a mutated Huntingtin (HTT) gene containing an expans

Dystonia is a debilitating movement disorder characterized by abnormal movements and postures. Given the absence of structural lesions in the brain of most dystonic patients, disruption of synaptic function has been long hypothesized to play a pivotal role in dystonia pathogenesis. We recently identified homozygous frameshift, nonsense, and missense variants in TSPOAP1, the gene encoding active zone RIM-binding protein 1 (RIMBP1), as a novel genetic cause of autosomal recessive dystonia (Mencacci et al., JCI, 2021). RIMBP1 is a presynaptic protein that localizes voltage-gated Ca2+ channels (VG

Most animals evolved with bilateral symmetry. Yet, many behaviors, from tying shoelaces to playing sports, require asymmetric motions and frequent transitions between the use of different sides of the body. Sidedness (whether the movement is produced on the right or left side of the body) therefore constitutes a critical aspect of the behavior, in addition to the sequence of actions that compose a behavior. We do not know how neural circuits coordinate these two aspects of behavior in any system. To solve this problem, we take advantage of a quantifiable, yet complex behavior produced by Droso

…tools, in vivo two-photon imaging, and patch-clamp electrophysiology in Drosophila. We recently found that the axons of fly leg proprioceptors are o