No abstract

Stress exposure can produce profound change in physiology and behavior that can impair health and well-being. Of note, stress exposure is linked to anxiety disorders and depression in humans. The widespread impact of these disorders warrants investigation into treatments to mitigate the harmful effects of stress. Pharmacological treatments fail to help many with these disorders, so recent work has focused on non-pharmacological alternatives. One of the most promising of these alternatives is environmental enrichment (EE). In rodents, EE includes social, physical, and cognitive stimulation for the animal, in the form of larger cages, running wheels, and toys. EE successfully reduces the maladaptive effects of various stressors, both as treatment and prophylaxis. While we know that EE can have beneficial effects under stress conditions, the morphological and molecular mechanisms underlying these behavioral effects are still not well understood. EE is known to alter neurogenesis, dendrite development, and expression of neurotrophic growth factors, effects that vary by type of enrichment, age, and sex. To add to this complexity, EE has differential effects in different brain regions. Understanding how EE exerts its protective effects on morphological and molecular levels could hold the key to developing more targeted pharmacological treatments. In this review, we summarize the literature on the morphological and molecular consequences of EE and stress in key emotional regulatory pathways in the brain, the hippocampus, prefrontal cortex, and amygdala. The similarities and differences amongst these regions provide some insight into stress-EE interaction that may be exploited in future efforts toward prevention of, and intervention in, stress-related diseases.

The common molecular mechanisms underlying psychiatric disorders are not well understood. Prior attempts to assess the pathological mechanisms responsible for psychiatric disorders have been limited by biased selection of comparable disorders, datasets as well as challenges associated with data normalization. However, publicly available databases offer a unique opportunity to expand such investigations both in terms of the number and types of diseases. Here, we used DisGeNET, a database of over 24,000 gene-disease associations to investigate the similarities and dissimilarities associated with enrichment of pathways, cell-types, drug targets, and human chromosomes within an unbiased cluster of psychiatric disorders. We show that cognition and neurotransmission related pathways are involved across all disorders, whereas those associated with immune system and signal-response coupling (cell-surface receptors, signal-transduction, gene-expression, and metabolic process) are associated with few disorders of the cluster. The drug-target based enrichment confirms the involvement of neurotransmission related changes across these disorders. At cell-type level, dendrite targeting interneurons, across all layers, are most involved across all disorders. Finally, using a clustering-based similarity index, we showed that the similarity between the disorders are influenced most at chromosomal level and to some extent at cellular level. Collectively, the results provide a comprehensive comparison of many psychiatric diseases in an unbiased manner and expand our understanding of the cellular and molecular pathologies associated with similar and comorbid psychiatric disorders.

The common molecular mechanisms underlying psychiatric disorders are not well understood. Prior attempts to assess the pathological mechanisms responsible for psychiatric disorders have been limited by biased selection of comparable disorders, datasets/cohort availability, and challenges with data normalization. Here, using DisGeNET, a gene-disease associations database, we sought to expand such investigations in terms of number and types of diseases. In a top-down manner, we analyzed an unbiased cluster of 36 psychiatric disorders and comorbid conditions at biological pathway, cell-type, drug-target, and chromosome levels and deployed density index, a novel metric to quantify similarities (close to 1) and dissimilarities (close to 0) between these disorders at each level. At pathway level, we show that cognition and neurotransmission drive the similarity and are involved across all disorders, whereas immune-system and signal-response coupling (cell surface receptors, signal transduction, gene expression, and metabolic process) drives the dissimilarity and are involved with specific disorders. The analysis at the drug-target level supports the involvement of neurotransmission-related changes across these disorders. At cell-type level, dendrite-targeting interneurons, across all layers, are most involved. Finally, by matching the clustering pattern at each level of analysis, we showed that the similarity between the disorders is influenced most at the chromosomal level and to some extent at the cellular level. Together, these findings provide first insights into distinct cellular and molecular pathologies, druggable mechanisms associated with several psychiatric disorders and comorbid conditions and demonstrate that similarities between these disorders originate at the chromosome level and disperse in a bottom-up manner at cellular and pathway levels.

In psychiatric disorders, mismatches between disease-states and therapeutic strategies are highly pronounced, largely because of unanswered questions regarding specific vulnerabilities of different cell-types and therapeutic responses. Which cellular events (housekeeping or salient) are most affected? Which cell-types succumb first to challenges, and which exhibit the strongest response to drugs? Are these events coordinated between cell-types? How does the disease-state and drug affect this coordination? To address these questions, we analyzed single-nucleus-RNAseq (sn-RNAseq) data from the human anterior cingulate cortex-a region involved in many psychiatric disorders. Density index, a metric for quantifying similarities and dissimilarities across functional profiles, was employed to identify common (housekeeping) or salient functional themes across all cell-types. Cell-specific signatures were integrated with existing disease and drug-specific signatures to determine cell-type-specific vulnerabilities, druggabilities, and responsiveness. Clustering of functional profiles revealed cell-types jointly participating in these events. SST and VIP interneurons were found to be most vulnerable, whereas pyramidal neurons were least vulnerable. Overall, the disease-state is superficial layercentric, largely influences cell-specific salient themes, strongly impacts disinhibitory neurons, and influences astrocyte interaction with a subset of deep-layer pyramidal neurons. Drug activities, on the other hand, are deep layer-centric and involve activating a distinct subset of deep-layer pyramidal neurons to circumvent the disinhibitory circuit malfunctioning in the disease-state. These findings demonstrate a novel application of sn-RNAseq data to explain drug and disease action at a systems level, suggests a targeted drug development and reevaluate various postmortem-based findings.

Animal models have expanded our understanding of temporal lobe epilepsy (TLE). However, translating these to cell-specific druggable hypotheses is not explored. Herein, we conducted an integrative insilico-analysis of an available transcriptomics dataset obtained from animals with pilocarpine-induced-TLE. A set of 119 genes with subtle-to-moderate impact predicted most forms of epilepsy with ~ 97% accuracy and characteristically mapped to upregulated homeostatic and downregulated synaptic pathways. The deconvolution of cellular proportions revealed opposing changes in diverse cell types. The proportion of nonneuronal cells increased whereas that of interneurons, except for those expressing vasoactive intestinal peptide (Vip), decreased, and pyramidal neurons of the cornu-ammonis (CA) subfields showed the highest variation in proportion. A probabilistic Bayesian-network demonstrated an aberrant and oscillating physiological interaction between nonneuronal cells involved in the blood–brain-barrier and Vip interneurons in driving seizures, and their role was evaluated insilico using transcriptomic changes induced by valproic-acid, which showed opposing effects in the two cell-types. Additionally, we revealed novel epileptic and antiepileptic mechanisms and predicted drugs using causal inference, outperforming the present drug repurposing approaches. These well-powered findings not only expand the understanding of TLE and seizure oscillation, but also provide predictive biomarkers of epilepsy, cellular and causal micro-circuitry changes associated with it, and a drug-discovery method focusing on these events.

RNA expression and protein abundance are often at odds when measured in parallel, raising questions about the functional implications of transcriptomics data. Here, we present the concept of persistence, which attempts to address this challenge by combining protein half-life data with RNA expression into a single metric that approximates protein abundance. The longer a protein’s half-life, the more influence it can have on its surroundings. This data offers a valuable opportunity to gain deeper insight into the functional meaning of transcriptome changes. We demonstrate the application of persistence using schizophrenia (SCZ) datasets, where it greatly improved our ability to predict protein abundance from RNA expression. Furthermore, this approach successfully identified persistent genes and pathways known to have impactful changes in SCZ. These results suggest that persistence is a valuable metric for improving the functional insight offered by transcriptomics data, and extended application of this concept could advance numerous research fields.

Central cholinergic systems regulate the hypothalamic-pituitary-adrenal (HPA) axis differentially in males and females (sexual diergism). We previously investigated the role of muscarinic receptors in this regulation by administering physostigmine (PHYSO), an acetylcholinesterase inhibitor, to male and female rats pretreated with scopolamine (SCOP), a nonselective muscarinic antagonist. SCOP pretreatment enhanced adrenocorticotropic hormone (ACTH) and corticosterone (CORT) responses in both sexes, but males had greater ACTH responses while females had greater CORT responses. In the present study, we further explored the role of muscarinic receptor subtypes in HPA axis regulation by administering PHYSO to male and female rats following SCOP or various doses of either the M1 or the M2 selective muscarinic receptor antagonists, pirenzepine (PIREN) or methoctramine (METHO). Blood was sampled before and at multiple times after PHYSO. ACTH and CORT were determined by highly specific immunoassays. M1 antagonism by PIREN prior to PHYSO resulted in sustained, dose-dependent increases in ACTH and CORT: ACTH responses were similar in both sexes, and CORT responses were greater in females. M2 antagonism by METHO prior to PHYSO resulted in overall decreases in ACTH and CORT: ACTH and CORT responses were higher in females but lower in both sexes than the hormone responses following PIREN or SCOP pretreatment. Area under the curve analyses supported these findings. These results suggest that specific muscarinic receptor subtypes differentially influence the HPA axis in a sexually diergic manner.