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The thalamic reticular nucleus (TRN) is a GABAergic nucleus that encapsulates the entire thalamus and is the primary source of inhibition for the thalamus. The TRN’s extensive connection within the thalamocortical loop and physiological functions have led researchers to describe the TRN as a “guard” of the gateway for the flow of information. From attentional modulation to memory consolidation, the TRN has been demonstrated to play a central role in these cognitive functions. The disruption of these cognitive functions are commonly seen within neurodevelopmental disorders like schizophrenia with a growing amount of evidence linking the TRN as a potential candidate integral for the pathophysiology. Most studies focus on the physiological properties and functions of the TRN however, there are major gaps in our understanding of the organization and the connection between morphology, neurochemistry, and physiology within the TRN. In this study, we investigate the molecular composition and expression of calretinin and SMI-32 within the TRN in non-human primates, postmortem human controls, and postmortem schizophrenia patients. Calretinin and SMI-32 are both neuroproteins that have been identified in unique populations within the TRN however the neuronal characteristics of these subpopulations have yet to be explored. We conducted quantitative analysis to estimate the population, density, and distribution of these neurons as well as morphological characteristics in distinct TRN sectors. Additionally, we investigated whether the expression of calretinin and parvalbumin are found in isolated and/or overlapping populations and where those distributions are present. We observed that the TRN is a heterogenous structure with continuous variation in the distributions and densities of CR and SMI-32. The features between non-human primate and human TRN are generally consistent in distribution patterns however the human TRN was observed to have decreased neuronal density and increased neuron size. Additionally, we observed an increase in both neuronal size and density within schizophrenia potentially identifying a possible dysfunction within the thalamocortical loop. Together these results will help further our understanding and the distinction between normal and pathological physiology which is a prerequisite for building biologically plausible computational models of diseased brains. / 2025-05-30T00:00:00Z

The study of consciousness is fundamental to understanding how the brain processes information. Over the years, many research studies have undertaken the task of dissociating the mechanisms underlying the processing of conscious and unconscious information. Neural oscillations are fundamental to information processing and communication in the brain. While many studies have shown a correlational and causational role of these neural oscillations for the maintenance of conscious information, there exists a dearth of causational studies that show the dissociable role of neural oscillations in the processing of unconscious information. In this study, we used high-definition transcranial alternating current stimulations to entrain the bilateral occipital regions of the brain with alpha, beta, or theta rhythms while participants performed a delayed target-probe discrimination task. Through neuromodulation, we showed that entrainment of beta rhythms improved the participants’ performance in trials reported as ‘seen’ or conscious by facilitating the short-term memory for task relevant information. On the other hand, alpha modulation enhanced participants’ performance in trials reported as ‘unseen’ or unconscious which has not been predicted by any existing consciousness theories.

While the proportion of aged individuals is increasing across populations, therapeutic advances have resulted in a particular increase amongst aged persons living with HIV, who maintain an elevated risk for developing HIV-Associated Neurological Deficits (HANDs). To determine the neurobiological mechanisms of HAND, the current experiments assessed if mechanistic insights from Alzheimer’s Disease, such as oxidative stress and protein quality control (i.e. stress granules, BAG chaperones), may similarly contribute to neuronal dysfunction in response to HIV proteins Tat and Nef. Although data indicate limited effects on stress granules, Tat and Nef facilitated elevations in intraneuronal oxidative stress, decreased BAG1 transcription and suppressed BAG3 levels (i.e. protein and RNA), while these disrupted mechanisms coincided with impaired electrophysiological firing capacities in neurons. Oxidative stress, in the form of H2O2, exacerbated the reduction in BAG3, induced an upregulation of BAG1 and dysregulated key mitochondrial proteins. Such inverse BAG chaperone ratios were maintained in two animal models which express viral proteins in the CNS, the doxycycline-inducible Tat (iTat) and Tg26 mouse. Interestingly, the inhibition of oxidative stress in primary neurons was capable of partially preserving electrophysiological functioning and BAG3 levels otherwise altered by HIV viral proteins. Results suggest oxidative stress induced by HIV proteins or other factors (i.e. aging) may dysregulate neuronal PQC, particularly BAG chaperones, and contribute to the neurobiological mechanisms underlying HAND. / Psychology

Tauopathies are a class of sporadic neurodegenerative disorders including Alzheimer’s disease (AD), Pick’s disease, Corticobasal degeneration and Progressive supranuclear palsy, characterized by hyperphosphorylation and aggregation of the microtubule-associated protein tau in the brain parenchyma. Currently, there are no effective therapies for the treatment of tauopathies and the understanding of its pathogenesis is still incomplete. Despite in recent years, miRNAs dysregulation has been constantly reported in Alzheimer’s disease (AD) and related tauopathies, the fundamental challenge of the current research is to understand whether these miRNA changes contribute to the onset and progression of these disorders or instead occur as a secondary event to tau pathology. Due to the ability of miRNAs to modulate disease-related gene networks, we hypothesized that dysregulation of these small molecules promotes abnormal tau phosphorylation and aggregation and that the restoration of their normal level of expression represents a valuable therapeutic approach for the treatment of these disorders. To test our hypothesis, we investigated the temporal and regional specific miRNAs expression profile and its association with the onset and/or progression of tau pathology in the mouse model that currently, best recapitulates the human condition. In addition, we explored the pathophysiological mechanisms regulated by the screened miRNAs in vitro and the feasibility of using miRNAs as therapeutic targets for the treatment of tauopathies. Compared with age-matched control, we found three specific miRNAs (miR-132-3p, miIR-146a-5p, miR-22-3p) significantly upregulated already in the pre-symptomatic stage in the hTau mice, and the investigation of their predicted targets highlighted pathways relevant to neuronal survival and synaptic function. In vitro mechanistic studies demonstrated that, miR-22-3p promotes increased levels of total soluble, MC1-conformational change and insoluble tau via dysregulation of the cell cycle and inhibition of the autophagy pathway. Moreover, for the first time we report miR-22-3p upregulation also in the cortex of Pick’s patients. Finally, we demonstrated that downregulation of endogenous miR-22-3p rescued tau phosphorylation and conformational change in the hTau mouse model of tauopathy. In conclusion, this study provides new clues ino the relationship between miRNAs dysregulation and tau protein and highlights the potentially beneficial effect of targeting miRNA molecules for the treatment of tauopathies. / Biomedical Neuroscience

The Polyomavirus JC (JCV) causes the demyelinating disease progressive multifocal leukoencephalopathy (PML). Infection by JCV is very common in childhood after which the virus enters a latent state, the mechanisms of which are poorly understood. Under conditions of severe immunosuppression, especially acquired immunodeficiency syndrome (AIDS), JCV may reactivate to cause PML. JC viral proteins expression is regulated by the JCV non-coding control region (NCCR), which contains binding sites for cellular transcriptional factors which regulate JCV transcription. Our earlier studies indicate that reactivation occurs within glial cells due to the action of cytokines such as TNF-⍺, which stimulate viral gene expression. In this study, we have examined the role of cytokines interferon-⍺ or -β which, in contrast, have a negative effect on JCV transcriptional regulation. Treatment of glial cells with interferon-⍺ or -β increased the endogenous level of C/EBPβ-LIP in a time-dependent manner. Furthermore, the negative regulatory role of interferon-⍺ or -β in JCV early and late transcription and viral replication was more pronounced in the presence of C/EBPβ-LIP. Knock-down of C/EBPβ-LIP (liver inhibitory protein) by shRNA targeting C/EBPβ-LIP reversed the inhibitory effect on JCV viral replication. Therefore, these data suggest that interferon-⍺ or -β negatively regulates JCV through induction of C/EBPβ-LIP, which together with other cellular transcriptional factors may control the balance between JCV latency and activation leading to PML. This balance may be regulated by proinflammatory cytokines in the brain, such as IFN-?. / Biomedical Neuroscience

Neurodegenerative disorders occur when neurons, in the brain and spinal cord, begin to decline. Instabilities in these cells cause them to function irregularly and eventually result in death. A subset of these diseases is called tauopathies. Tauopathies are characterized by a filamentous accumulation of hyper-phosphorylated tau, in neurons and glial cells. Currently, it is unknown how tau becomes hyper-phosphorylated and/or it accumulates in the brain. Tau is a highly soluble natively unfolded protein, closely associated with the proper functioning of the cytoskeletal network. However, in tauopathies, tau becomes an insoluble protein that forms intracellular fibrillar deposits in neurons and glial cells. Studies have shown that there is a direct relationship between the abnormal increase in tau phosphorylation, the cell cycle, and MiRNA-22-3p. There have been several strategies and targets developed in order to treat tauopathies, but there are no known consistent, effective treatments. Recently, miRNAs have emerged as a potential target to manipulate the tau protein. MiRNAs are small noncoding RNAs, that control major cellular functions by binding to the 3’ untranslated region of messenger RNAs, causing inhibition of their translation or promoting their degradation. We have hypothesized that miRNA-22-3p halts abnormal tau phosphorylation levels, in brain endothelial cells. To test this hypothesis, we transfected a miRNA-22-3p mimic, into a brain endothelial cell line. Then, we ran a western blot experiment to look at the proteins, related to tau. We looked at total tau, tau phosphorylation at different epitopes, and P21, a cell cycle marker. Our data demonstrated that miRNA-22-3p halts abnormal tau phosphorylation. In conclusion, we have shown a relationship between miRNA-22-3p and tau phosphorylation. We have highlighted a possible therapeutic benefit that, when investigated further, could serve as a potential treatment on tauopathies and accentuated favorable targets against abnormal tau phosphorylation. We hope to be able to provide others with the information needed to manipulate miRNA-22-3p and downregulate the expression of the tau protein. / Biomedical Sciences

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