Hippocampal replay - the time-compressed, sequential reactivation of ensembles of neurons related to past experience - is a key neural mechanism of memory consolidation. Replay typically coincides with a characteristic pattern of local field potential activity, the sharp-wave ripple (SWR). Reduced SWR rates are associated with cognitive impairment in multiple models of neurodegenerative disease, suggesting that a clinically viable intervention to promote SWRs and replay would prove beneficial. We therefore developed a neurofeedback paradigm for rat subjects in which SWR detection triggered rapid positive feedback in the context of a memory-dependent task. This training protocol increased the prevalence of task-relevant replay during the targeted neurofeedback period by changing the temporal dynamics of SWR occurrence. This increase was also associated with neural and behavioral forms of compensation after the targeted period. These findings reveal short-timescale regulation of SWR generation and demonstrate that neurofeedback is an effective strategy for modulating hippocampal replay.

Aestivation and hibernation represent distinct forms of animal quiescence, characterized by physiological changes, including ion composition. Intracellular ion flows play a pivotal role in eliciting alterations in membrane potential and facilitating cellular communication, while outward K+ currents aid in the restitution and upkeep of the resting membrane potential. This study explores the relationship between inward and outward currents during aestivation in Achatina fulica snails. Specimens were collected near MSUBIT University in Shenzhen and divided into two groups. The first group was kept on a lattice diet, while the second one consisted of aestivating individuals, that were deprived of food and water until a cork-like structure sealed their shells. Recording of current from isolated neurons were conducted using the single-electrode voltage clamp mode with an AxoPatch 200B amplifier. Electrophysiological recordings on pedal ganglia neurons revealed significant differences in the inactivation processes of the Ia and Ikdr components. Alterations in the Ikdr component may inhibit pacemaker activity in pedal ganglion neurons, potentially contributing to locomotion cessation in aestivated animals. The KS current remains unaffected during aestivation. Changes in slow K+ current components could disrupt the resting membrane potential, possibly leading to cell depolarization and influx of Ca2+ and Na+ ions, impacting cell homeostasis. Thus, maintaining the constancy of outward K+ current is essential for cell stability.

The genetic architecture of Parkinson\'s disease (PD) is complex and multiple brain cell subtypes are involved in the neuropathological progression of the disease. Here we aimed to advance our understanding of PD genetic complexity at a cell subtype precision level. Using parallel single-nucleus (sn)RNA-seq and snATAC-seq analyses we simultaneously profiled the transcriptomic and chromatin accessibility landscapes in temporal cortex tissues from 12 PD compared to 12 control subjects at a granular single cell resolution. An integrative bioinformatic pipeline was developed and applied for the analyses of these snMulti-omics datasets. The results identified a subpopulation of cortical glutamatergic excitatory neurons with remarkably altered gene expression in PD, including differentially-expressed genes within PD risk loci identified in genome-wide association studies (GWAS). This was the only neuronal subtype showing significant and robust overexpression of SNCA. Further characterization of this neuronal-subpopulation showed upregulation of specific pathways related to axon guidance, neurite outgrowth and post-synaptic structure, and downregulated pathways involved in presynaptic organization and calcium response. Additionally, we characterized the roles of three molecular mechanisms in governing PD-associated cell subtype-specific dysregulation of gene expression: (1) changes in cis-regulatory element accessibility to transcriptional machinery; (2) changes in the abundance of master transcriptional regulators, including YY1, SP3, and KLF16; (3) candidate regulatory variants in high linkage disequilibrium with PD-GWAS genomic variants impacting transcription factor binding affinities. To our knowledge, this study is the first and the most comprehensive interrogation of the multi-omics landscape of PD at a cell-subtype resolution. Our findings provide new insights into a precise glutamatergic neuronal cell subtype, causal genes, and non-coding regulatory variants underlying the neuropathological progression of PD, paving the way for the development of cell- and gene-targeted therapeutics to halt disease progression as well as genetic biomarkers for early preclinical diagnosis.

The potential long-term effects of anesthesia on cognitive development, especially in neonates and infants, have raised concerns. However, our understanding of its underlying mechanisms and effective treatments is still limited. In this study, we found that early exposure to isoflurane (ISO) impaired fear memory retrieval, which was reversed by dexmedetomidine (DEX) pre-treatment. Measurement of c-fos expression revealed that ISO exposure significantly increased neuronal activation in the zona incerta (ZI). Fiber photometry recording showed that ZI neurons from ISO mice displayed enhanced calcium activity during retrieval of fear memory compared to the control group, while DEX treatment reduced this enhanced calcium activity. Chemogenetic inhibition of ZI neurons effectively rescued the impairments caused by ISO exposure. These findings suggest that the ZI may play a pivotal role in mediating the cognitive effects of anesthetics, offering a potential therapeutic target for preventing anesthesia-related cognitive impairments.

Dysbindin-1, a protein encoded by the schizophrenia susceptibility gene DTNBP1, is reduced in the hippocampus of schizophrenia patients. It is expressed in various cellular populations of the brain and implicated in dopaminergic and glutamatergic transmission. To investigate the impact of reduced dysbindin-1 in excitatory cells on hippocampal-associated behaviors and synaptic transmission, we developed a conditional knockout mouse model with deletion of dysbindin-1 gene in CaMKIIα expressing cells. We found that dysbindin-1 reduction in CaMKII expressing cells resulted in impaired spatial and social memories, and attenuation of the effects of glutamate N-methyl-d-asparate receptor (NMDAR) antagonist MK801 on locomotor activity and prepulse inhibition of startle (PPI). Dysbindin-1 deficiency in CaMKII expressing cells also resulted in reduced protein levels of NMDAR subunit GluN1 and GluN2B. These changes were associated with increased expression of immature dendritic spines in basiliar dendrites and abnormalities in excitatory synaptic transmission in the ventral hippocampus. These results highlight the functional relevance of dysbindin-1 in excitatory cells and its implication in schizophrenia-related pathologies.

Cortical sensory processing is greatly impacted by internally generated activity. But controlling for that activity is difficult since the thalamocortical network is a high-dimensional system with rapid state changes. Therefore, to unwind the cortical computational architecture there is a need for physiological \'landmarks\' that can be used as frames of reference for computational state. Here we use a waveshape transform method to identify conspicuous local field potential sharp waves (LFP-SPWs) in the somatosensory cortex (S1). LFP-SPW events triggered short-lasting but massive neuronal activation in all recorded neurons with a subset of neurons initiating their activation up to 20 ms before the LFP-SPW onset. In contrast, LFP-SPWs differentially impacted the neuronal spike responses to ensuing tactile inputs, depressing the tactile responses in some neurons and enhancing them in others. When LFP-SPWs coactivated with more distant cortical surface (ECoG)-SPWs, suggesting an involvement of these SPWs in global cortical signaling, the impact of the LFP-SPW on the neuronal tactile response could change substantially, including inverting its impact to the opposite. These cortical SPWs shared many signal fingerprint characteristics as reported for hippocampal SPWs and may be a biomarker for a particular type of state change that is possibly shared byboth hippocampus and neocortex.

Attention supports decision making by selecting the features that are relevant for decisions. Selective enhancement of the relevant features and inhibition of distractors has been proposed as potential neural mechanisms driving this selection process. Yet, how attention operates when relevance cannot be directly determined, and the attention signal needs to be internally constructed is less understood. Here we recorded from populations of neurons in the anterior cingulate cortex (ACC) of mice in an attention-shifting task where relevance of stimulus modalities changed across blocks of trials. In contrast with V1 recordings, decoding of the irrelevant modality gradually declined in ACC after an initial transient. Our analytical proof and a recurrent neural network model of the task revealed mutually inhibiting connections that produced context-gated suppression as observed in mice. Using this RNN model we predicted a correlation between contextual modulation of individual neurons and their stimulus drive, which we confirmed in ACC but not in V1.

Olfaction is influenced by contextual factors, past experiences, and the animal\'s internal state. Whether this information is integrated at the initial stages of cortical odour processing is not known, nor how these signals may influence odour encoding. Here we revealed multiple and diverse non-olfactory responses in the primary olfactory (piriform) cortex (PCx), which dynamically enhance PCx odour discrimination according to behavioural demands. We performed recordings of PCx neurons from mice trained in a virtual reality task to associate odours with visual contexts to obtain a reward. We found that learning shifts PCx activity from encoding solely odours to a regime in which positional, contextual, and associative responses emerge on odour-responsive neurons that become mixed-selective. The modulation of PCx activity by these non-olfactory signals was dynamic, improving odour decoding during task engagement and in rewarded contexts. This improvement relied on the acquired mixed-selectivity, demonstrating how integrating extra-sensory inputs in sensory cortices can enhance sensory processing while encoding the behavioural relevance of stimuli.

Addiction is a complex behavioral disorder characterized by compulsive drug-seeking and drug use despite harmful consequences. The prefrontal cortex (PFC) plays a crucial role in cocaine addiction, involving decision-making, impulse control, memory, and emotional regulation. The PFC interacts with the brain\'s reward system, including the ventral tegmental area (VTA) and nucleus accumbens (NAc). The PFC also projects to the lateral habenula (LHb), a brain region critical for encoding negative reward and regulating the reward system. In the current study, we examined the role of PFC-LHb projections in regulating cocaine reward-related behaviors. We found that optogenetic stimulation of the PFC-LHb circuit during cocaine conditioning abolished cocaine preference without causing aversion. In addition, increased c-fos expression in LHb neurons was observed in animals that received optic stimulation during cocaine conditioning, supporting the circuit\'s involvement in cocaine preference regulation. Molecular analysis in animals that received optic stimulation revealed that cocaine-induced alterations in the expression of GluA1 subunit of AMPA receptor was normalized to saline levels in a region-specific manner. Moreover, GluA1 serine phosphorylation on S845 and S831 were differentially altered in LHb and VTA but not in the PFC. Together these findings highlight the critical role of the PFC-LHb circuit in controlling cocaine reward-related behaviors and shed light on the underlying mechanisms. Understanding this circuit\'s function may provide valuable insights into addiction and contribute to developing targeted treatments for substance use disorders.

UNASSIGNED: Responding to social signals by expressing the correct behavior is not only challenged in autism, but also in diseases with high prevalence of autism, like Prader-Willi Syndrome (PWS). Clinical evidence suggests aberrant pro-social behavior in patients can be regulated by intranasal oxytocin (OXT) or vasopressin (AVP). However, what neuronal mechanisms underlie impaired behavioral responses in a socially-aversive context, and how can they be corrected, remains largely unknown.
UNASSIGNED: Using the Magel2 knocked-out (KO) mouse model of PWS (crossed with CRE-dependent transgenic lines), we devised optogenetic, physiological and pharmacological strategies in a social-fear-conditioning paradigm. Pathway specific roles of OXT and AVP signaling were investigated converging on the lateral septum (LS), a region which receives dense hypothalamic inputs.
UNASSIGNED: OXT and AVP signaling promoted inhibitory synaptic transmission in the LS, which failure in Magel2KO mice disinhibited somatostatin (SST) neurons and disrupted social-fear extinction. The source of OXT and AVP deficits mapped specifically in the supraoptic nucleus→LS pathway of Magel2KO mice disrupting social-fear extinction, which could be corrected by optogenetic or pharmacological inhibition of SST-neurons in the LS. Interestingly, LS SST-neurons also gated the expression of aggressive behavior, possibly as part of functional units operating beyond local septal circuits.
UNASSIGNED: SST cells in the LS play a crucial role in integration and expression of disrupted neuropeptide signals in autism, thereby altering the balance in expression of safety versus fear. Our results uncover novel mechanisms underlying dysfunction in a socially-aversive context, and provides a new framework for future treatments in autism-spectrum disorders.