Associative learning genetic circuits

Errors of cerebellar development are increasingly acknowledged as risk factors for neuro-developmental disorders (NDDs), such as attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and schizophrenia. Evidence has been assembled from cerebellar abnormalities in autistic patients, as well as a range of genetic mutations identified in human patients that affect the cerebellar circuit, particularly Purkinje cells, and are associated with deficits of motor function, learning and social behavior; traits that are commonly associated with autism and schizophrenia...

Over the past 20 years there has been an increasing number of brain imaging studies on the mechanisms underlying reward motivation in humans. This narrative review describes studies on the neural mechanisms associated with reward motivation and their relationships with cognitive function in healthy human participants. The brain's meso-limbic dopamine reward circuitry in humans is known to control reward-motivated behavior in humans. The medial and lateral Pre-Frontal Cortex (PFC) integrate motivation and cognitive control during decision-making and the dorsolateral PFC (dlPFC) integrates and transmits signals of reward to the mesolimbic and meso-cortical dopamine circuits and initiates motivated behavior...

Habituation is a foundational learning process critical for animals to adapt their behavior to changes in their sensory environment. Although habituation is considered a simple form of learning, the identification of a multitude of molecular pathways including several neurotransmitter systems that regulate this process suggests an unexpected level of complexity. How the vertebrate brain integrates these various pathways to accomplish habituation learning, whether they act independently or intersect with one another, and whether they act via divergent or overlapping neural circuits has remained unclear...

The relationship between genotype and phenotype in DYT-TOR1A dystonia as well as the associated motor circuit alterations are still insufficiently understood. DYT-TOR1A dystonia has a remarkably reduced penetrance of 20-30%, which has led to the second-hit hypothesis emphasizing an important role of extragenetic factors in the symptomatogenesis of TOR1A mutation carriers. To analyze whether recovery from a peripheral nerve injury can trigger a dystonic phenotype in asymptomatic hΔGAG3 mice, which overexpress human mutated TorsinA, a sciatic nerve crush was applied...

Allosteric transcription factor (aTF) based biosensors can be used to engineer genetic circuits for a wide range of applications. The literature and online databases contain hundreds of experimentally validated molecule-TF pairs; however, the knowledge is scattered and often incomplete. Additionally, compared to the number of compounds that can be produced in living systems, those with known associated TF-compound interactions are low. For these reasons, new tools that help researchers find new possible TF-ligand pairs are called for...

BACKGROUND: Neuropsychology and imaging changes have been reported in the preclinical stage of familial Alzheimer's disease (FAD). This study investigated the effects of APOEε4 and known pathogenic gene mutation on different cognitive domains and circuit imaging markers in preclinical FAD. METHODS: One hundred thirty-nine asymptomatic subjects in FAD families, including 26 APOEε4 carriers, 17 APP and 20 PS1 mutation carriers, and 76 control subjects, went through a series of neuropsychological tests and MRI scanning...

UNLABELLED: Mutations in MECP2 cause the neurodevelopmental disorder Rett syndrome. MECP2 codes for methyl CpG binding protein 2 (MECP2), a transcriptional regulator that activates genetic programs for experience-dependent plasticity. Many neural and behavioral symptoms of Rett syndrome may result from dysregulated timing and threshold for plasticity. As a model of adult plasticity, we examine changes to auditory cortex inhibitory circuits in female mice when they are first exposed to pups; this plasticity facilitates behavioral responses to pups emitting distress calls...

Ethanol tolerance is the first type of behavioral plasticity and neural plasticity that is induced by ethanol intake, and yet its molecular and circuit bases remain largely unexplored. Here, we characterize three distinct forms of ethanol tolerance in male Drosophila: rapid, chronic, and repeated. Rapid tolerance is composed of two short-lived memory-like states, one that is labile and one that is consolidated. Chronic tolerance, induced by continuous exposure, lasts for two days, induces ethanol preference, and hinders the development of rapid tolerance through the activity of histone deacetylases (HDACs)...

Learning has been associated with modifications of synaptic and circuit properties, but the precise changes storing information in mammals have remained largely unclear. We combined genetically targeted voltage imaging with targeted optogenetic activation and silencing of pre- and post-synaptic neurons to study the mechanisms underlying hippocampal behavioral timescale plasticity. In mice navigating a virtual-reality environment, targeted optogenetic activation of individual CA1 cells at specific places induced stable representations of these places in the targeted cells...

High-throughput anatomical data can stimulate and constrain new hypotheses about how neural circuits change in response to experience. Here we use fluorescence-based reagents for pre- and postsynaptic labeling to monitor changes in thalamocortical synapses onto different compartments of layer 5 (L5) pyramidal (Pyr) neurons in somatosensory (barrel) cortex from mixed-sex mice during whisker-dependent learning (Audette et al., 2019). Using axonal fills and molecular-genetic tags for synapse identification in fixed tissue from Rbp4-Cre transgenic mice, we found that thalamocortical synapses from the higher-order posterior medial (POm) thalamic nucleus showed rapid morphological changes in both pre- and postsynaptic structures at the earliest stages of sensory association training...

Generating adaptive behavioral responses to emotionally salient stimuli requires evaluation of complex associations between multiple sensations, the surrounding context, and current internal state. Neural circuits within the amygdala parse this emotional information, undergo synaptic plasticity to reflect learned associations, and evoke appropriate responses through their projections to the brain regions orchestrating these behaviors. Information flow within the amygdala is regulated by the intercalated cells (ITCs), which are densely packed clusters of GABAergic neurons that encircle the basolateral amygdala (BLA) and provide contextually relevant feedforward inhibition of amygdala nuclei, including the central and BLA...

One challenge in the engineering of biological systems is to be able to recognise the cellular stress states of bacterial hosts, as these stress states can lead to suboptimal growth and lower yields of target products. To enable the design of genetic circuits for reporting or mitigating the stress states, it is important to identify a relatively reduced set of gene biomarkers that can reliably indicate relevant cellular growth states in bacteria. Recent advances in high-throughput omics technologies have enhanced the identification of molecular biomarkers specific states in bacteria, motivating computational methods that can identify robust biomarkers for experimental characterisation and verification...

Genetically tractable animal models provide needed strategies to resolve the biological basis of drug addiction. Intravenous self-administration (IVSA) is the gold standard for modeling psychostimulant and opioid addiction in animals, but technical limitations have precluded the widespread use of IVSA in mice. Here, we describe IVSA paradigms for mice that capture the multi-stage nature of the disorder and permit predictive modeling. In these paradigms, C57BL/6J mice with long-standing indwelling jugular catheters engaged in cocaine- or remifentanil-associated lever responding that was fixed ratio-dependent, dose-dependent, extinguished by withholding the drug, and reinstated by the presentation of drug-paired cues...

Twice-exceptional learners face a unique set of challenges arising from the intersection of extraordinary talent and disability. Neurobiology research has the capacity to complement pedagogical research and provide support for twice-exceptional learners. Very few studies have attempted to specifically address the neurobiological underpinnings of twice-exceptionality. However, neurobiologists have built a broad base of knowledge in nervous system function spanning from the level of neural circuits to the molecular basis of behavior...

The principles of how brain circuits establish themselves during development are largely conserved across animal species. Connections made during embryonic development that are appropriate for an early life stage are frequently remodelled later in ontogeny via pruning and subsequent regrowth to generate adult-specific connectivity. The mushroom body of the fruit fly Drosophila melanogaster is a well-established model circuit for examining the cellular mechanisms underlying neurite remodelling. This central brain circuit integrates sensory information with learned and innate valences to adaptively instruct behavioural decisions...

Cognitive impairment is highly prevalent in patients with major psychiatric disorders (MPDs), including schizophrenia (SCZ), bipolar disorder, major depressive disorder, in whom it can be highly disruptive to community functioning and worsen prognosis. Previously, genetic factors and cognitive impairments in MPD patients have been examined mostly in isolated circuits rather than in the whole brain. In the present study, genetic, neuroimaging, and psychometric approaches were combined to investigate the relationship among genetic factors, alterations throughout the brain, and cognitive impairments in a large cohort of patients diagnosed with SCZ, with a reference healthy control (HC) group...

Growing evidence suggests that Rho GTPases and molecules involved in their signaling pathways play a major role in the development of the central nervous system (CNS). Whole exome sequencing (WES) and de novo examination of mutations, including SNP (Single Nucleotide Polymorphism) in genes coding for the molecules of their signaling cascade, has allowed the recent discovery of dominant autosomic mutations and duplication or deletion of candidates in the field of neurodevelopmental diseases (NDD). Epidemiological studies show that the co-occurrence of several of these neurological pathologies may indeed be the rule...

The hippocampus is one of the most widely investigated brain regions with its massive contributions to multiple behaviours. Especially, the hippocampus is subdivided into the dorsal and ventral parts playing distinct roles. In this review, we will focus on the ventral hippocampus, especially the ventral CA1 (vCA1), whose role is being actively discovered. vCA1 is well known to be associated with emotion-like behaviour, in both positive (reward) and negative (aversive) stimuli. How can this small region in volume mediate such variety of responses? This question will be answered with technologies up to date that have allowed us to study in-depth the specific neural circuit and to map the complex connectivity...

Dopamine is a catecholamine neuromodulator implicated in locomotion, motivation, learning and cognitive behaviors. Although striatal dopamine signaling and circuitry are well established, the role of cortical dopamine projection circuitry in regulating striatal dopamine dynamics and behavior is not clear. Glutamatergic pyramidal neurons in the prefrontal cortex (PFC) are topographically organized and dopamine D1 and D2 receptors are expressed on glutamatergic pyramidal neurons in the PFC. Using a retrograde adeno-associated virus (AAVRG)-based approach we show that D1R+ subpopulations in medial orbitofrontal or prelimbic regions project to nucleus accumbens core (NAcc) or dorsal striatum (dSTR), respectively...

Cervical cancer is a global public health subject as it affects women in the reproductive ages, and accounts for the second largest burden among cancer patients worldwide with an unforgiving 50% mortality rate. Relatively scant awareness and limited access to effective diagnosis have led to this enormous disease burden, calling for point-of-care, minimally invasive diagnosis methods. Here, an end-to-end quantitative unified pipeline for diagnosis has been developed, beginning with identification of optimal biomarkers, concurrent design of toehold switch sensors, and finally simulation of the designed diagnostic circuits to assess performance...