Sex differences in neuronal oscillatory activity and memory in the methylazoxymethanol acetate model of schizophrenia.

The methylazoxymethanol acetate (MAM) rodent model is used to study aspects of schizophrenia. However, numerous studies that have employed this model have used only males, resulting in a dearth of knowledge on sex differences in brain function and behaviour. The purpose of this study was to determine whether differences exist between male and female MAM rats in neuronal oscillatory function within and between the prefrontal cortex (PFC), ventral hippocampus (vHIP) and thalamus, behaviour, and in proteins linked to schizophrenia neuropathology. We showed that female MAM animals exhibited region-specific alterations in theta power, elevated low and high gamma power in all regions, and elevated PFC-thalamus high gamma coherence. Male MAM rats had elevated beta and low gamma power in PFC, and elevated vHIP-thalamus coherence. MAM females displayed impaired reversal learning whereas MAM males showed impairments in spatial memory. Glycogen synthase kinase-3 (GSK-3) was altered in the thalamus, with female MAM rats displaying elevated GSK-3α phosphorylation. Male MAM rats showed higher expression and phosphorylation GSK-3α, and higher expression of GSK-ß. Sex-specific changes in phosphorylated Tau levels were observed in a region-specific manner. These findings demonstrate there are notable sex differences in behaviour, oscillatory network function, and GSK-3 signaling in MAM rats, thus highlighting the importance of inclusion of both sexes when using this model to study schizophrenia.

Nrf2 activation rescues stress-induced depression-like behaviour and inflammatory responses in male but not female rats.

BACKGROUND: Major depressive disorder (MDD) is a recurring affective disorder that is two times more prevalent in females than males. Evidence supports immune system dysfunction as a major contributing factor to MDD, notably in a sexually dimorphic manner. Nuclear factor erythroid 2-related factor 2 (Nrf2), a regulator of antioxidant signalling during inflammation, is dysregulated in many chronic inflammatory disorders; however, its role in depression and the associated sex differences have yet to be explored. Here, we investigated the sex-specific antidepressant and immunomodulatory effects of the potent Nrf2 activator dimethyl fumarate (DMF), as well as the associated gene expression profiles. METHODS: Male and female rats were treated with vehicle or DMF (25 mg/kg) whilst subjected to 8 weeks of chronic unpredictable stress. The effect of DMF treatment on stress-induced depression- and anxiety-like behaviours, as well as deficits in recognition and spatial learning and memory were then assessed. Sex differences in hippocampal (HIP) microglial activation and gene expression response were also evaluated. RESULTS: DMF treatment during stress exposure had antidepressant effects in male but not female rats, with no anxiolytic effects in either sex. Recognition learning and memory and spatial learning and memory were impaired in chronically stressed males and females, respectively, and DMF treatment rescued these deficits. DMF treatment also prevented stress-induced HIP microglial activation in males. Conversely, females displayed no HIP microglial activation associated with stress exposure. Last, chronic stress elicited sex-specific alterations in HIP gene expression, many of which were normalized in animals treated with DMF. Of note, most of the differentially expressed genes in males normalized by DMF were related to antioxidant, inflammatory or immune responses. CONCLUSIONS: Collectively, these findings support a greater role of immune processes in males than females in a rodent model of depression. This suggests that pharmacotherapies that target Nrf2 have the potential to be an effective sex-specific treatment for depression.

Major depressive disorder is two times more prevalent in females than males. Further, immune system dysfunction has been shown to contribute to the development of depression, with previous studies consistently reporting chronic low-grade inflammation in depressed individuals. Not surprisingly, the immune system dysfunction associated with depression appears to be sex specific. As such, whilst anti-inflammatory drugs have shown antidepressant effects in preclinical studies, the sex differences in these effects are seldomly investigated. Thus, this study sought to determine the sex-specific antidepressant and cognitive effects of dimethyl fumarate (DMF) treatment. DMF is a drug that activates the protein nuclear factor erythroid 2-related factor 2 to initiate anti-inflammatory processes. Here, male and female rats were exposed to 8 weeks of chronic stress whilst receiving daily DMF treatment. Subsequently, their expression of depression- and anxiety-like behaviours, as well as learning and memory deficits were assessed. Alterations in gene expression were also evaluated. DMF treatment had antidepressant effects in male rats only but did not have anti-anxiety effects in either sex. The learning and memory deficits in both sexes were rescued with DMF treatment. Notably, DMF normalized several of the sex-specific gene alterations induced by chronic stress, with many of the male-specific genes relating to inflammatory processes. These data suggest that DMF may be an effective antidepressant treatment in males.

A journey with psychedelic mushrooms: From historical relevance to biology, cultivation, medicinal uses, biotechnology, and beyond.

Psychedelic mushrooms containing psilocybin and related tryptamines have long been used for ethnomycological purposes, but emerging evidence points to the potential therapeutic value of these mushrooms to address modern neurological, psychiatric health, and related disorders. As a result, psilocybin containing mushrooms represent a re-emerging frontier for mycological, biochemical, neuroscience, and pharmacology research. This work presents crucial information related to traditional use of psychedelic mushrooms, as well as research trends and knowledge gaps related to their diversity and distribution, technologies for quantification of tryptamines and other tryptophan-derived metabolites, as well as biosynthetic mechanisms for their production within mushrooms. In addition, we explore the current state of knowledge for how psilocybin and related tryptamines are metabolized in humans and their pharmacological effects, including beneficial and hazardous human health implications. Finally, we describe opportunities and challenges for investigating the production of psychedelic mushrooms and metabolic engineering approaches to alter secondary metabolite profiles using biotechnology integrated with machine learning. Ultimately, this critical review of all aspects related to psychedelic mushrooms represents a roadmap for future research efforts that will pave the way to new applications and refined protocols.

A Simple, Lightweight, and Low-Cost Customizable Multielectrode Array for Local Field Potential Recordings.

Local field potential (LFP) recording is a valuable method for assessing brain systems communication. Multiple methods have been developed to collect LFP data to study the rhythmic activity of the brain. These methods range from the use of single or bundled metal electrodes to electrode arrays that can target multiple brain regions. Although these electrodes are efficient in collecting LFP activity, they can be expensive, difficult to build, and less adaptable to different applications, which may include targeting multiple brain regions simultaneously. Here, the building process for a 16-channel customizable multielectrode array (CMEA) that can be used to collect LFP data from different brain regions simultaneously in rats is described. These CMEA electrode arrays are lightweight (<1 g), take little time to build (<1 h), and are affordable ($15 Canadian). The CMEA can also be modified to record single-unit and multiunit activity in addition to LFP activity using both wired and wireless neural data acquisition systems. Moreover, these CMEAs can be used to explore neural activity (LFP and single-unit/multiunit activity) in preliminary studies, before purchasing more expensive electrodes for targeted studies. Together, these characteristics make the described CMEA a competitive alternative to the commercially available multielectrode arrays for its simplicity, low cost, and efficiency in collecting LFP data in freely behaving animals.

Bipolar disorder-iPSC derived neural progenitor cells exhibit dysregulation of store-operated Ca2+ entry and accelerated differentiation.

While most of the efforts to uncover mechanisms contributing to bipolar disorder (BD) focused on phenotypes at the mature neuron stage, little research has considered events that may occur during earlier timepoints of neurodevelopment. Further, although aberrant calcium (Ca2+) signaling has been implicated in the etiology of this condition, the possible contribution of store-operated Ca2+ entry (SOCE) is not well understood. Here, we report Ca2+ and developmental dysregulations related to SOCE in BD patient induced pluripotent stem cell (iPSC)-derived neural progenitor cells (BD-NPCs) and cortical-like glutamatergic neurons. First, using a Ca2+ re-addition assay we found that BD-NPCs and neurons had attenuated SOCE. Intrigued by this finding, we then performed RNA-sequencing and uncovered a unique transcriptome profile in BD-NPCs suggesting accelerated neurodifferentiation. Consistent with these results, we measured a slower rate of proliferation, increased neurite outgrowth, and decreased size in neurosphere formations with BD-NPCs. Also, we observed decreased subventricular areas in developing BD cerebral organoids. Finally, BD NPCs demonstrated high expression of the let-7 family while BD neurons had increased miR-34a, both being microRNAs previously implicated in neurodevelopmental deviations and BD etiology. In summary, we present evidence supporting an accelerated transition towards the neuronal stage in BD-NPCs that may be indicative of early pathophysiological features of the disorder.

Beyond the Binary: Gender Inclusivity in Schizophrenia Research.

Schizophrenia is a severe neuropsychiatric disorder with significant differences in the incidence and symptomology between cisgender men and women. In recent years, considerably more attention has been on the inclusion of sex and gender in schizophrenia research. However, the majority of this research has failed to consider gender outside of the socially constructed binary of men and women. As a result, little is known about schizophrenia in transgender and gender-nonconforming populations. In this review, we present evidence showing that transgender and gender-nonconforming individuals have elevated risk of developing schizophrenia, and we discuss minority stress theory and other potential factors that may contribute to this risk. The need for inclusion of transgender and gender-nonconforming communities in schizophrenia research is emphasized, alongside a discussion on considerations and challenges associated with this type of research. Finally, we offer specific strategies to make research on schizophrenia, and research on other neuropsychiatric disorders, more inclusive of those populations that do not fall within the socially constructed gender binary. If we are to succeed in the development of more personalized therapeutic approaches for all, a better understanding of the variability of the human brain is needed.

Cortical dopamine D5 receptors regulate neuronal circuit oscillatory activity and memory in rats.

INTRODUCTION: The dopamine D5 receptor (D5R) shows high expression in cortical regions, yet the role of the receptor in learning and memory remains poorly understood. This study evaluated the impact of prefrontal cortical (PFC) D5R knockdown in rats on learning and memory and assessed the role of the D5R in the regulation of neuronal oscillatory activity and glycogen synthase kinase-3 (GSK-3ß), processes integral to cognitive function. MATERIALS AND METHODS: Using an adeno-associated viral (AAV) vector, male rats were infused with shRNA to the D5R bilaterally into the PFC. Local field potential recordings were taken from freely moving animals and spectral power and coherence were evaluated in, and between, the PFC, orbitofrontal cortex (OFC), hippocampus (HIP), and thalamus. Animals were then assessed in object recognition, object location, and object in place tasks. The activity of PFC GSK-3ß, a downstream effector of the D5R, was evaluated. RESULTS: AAV-mediated knockdown of the D5R in the PFC induced learning and memory deficits. These changes were accompanied by elevations in PFC, OFC, and HIP theta spectral power and PFC-OFC coherence, reduced PFC-thalamus gamma coherence, and increased PFC GSK-3ß activity. CONCLUSION: This work demonstrates a role for PFC D5Rs in the regulation of neuronal oscillatory activity and learning and memory. As elevated GSK-3ß activity has been implicated in numerous disorders of cognitive dysfunction, this work also highlights the potential of the D5R as a novel therapeutic target via suppression of GSK-3ß.

Understanding and Rebalancing: A Rapid Scoping Review of Cannabis Research Among Indigenous People.

Evidence-based perspectives on and patterns of cannabis use are vital to addressing ethical, legal, and regulatory controversies, but have not yet been mapped for Indigenous people. We searched five databases and used a rapid scoping review methodology to analyze empirical studies with a primary focus on cannabis and Indigenous peoples. Studies were examined for year of publication, origin of study and author groups, methods, and thematic foci. We analyzed 68 studies with publication dates between1983 and 2022. Approximately 90% of articles were written by authors in the same geographic location as the study population. Seventy-one percent (71%) of the articles were written by authors of multiple articles. Four articles acknowledged author Indigeneity. None contained author positionality statements. The majority of studies utilized mixed methods that integrated both qualitative and quantitative components. Two major categories of focus that emerged from the analysis are substance use disorders and prevalence rates (n=35) and predictors of and motivators for use (n=27), together representing the majority of articles (n=52/68). Impact on mental health (n=6), treatment, and management of cannabis use disorder (CUD) (n=3), legalization and criminalization (n=2), genomic heritability and dependence (n=2), and economics of cannabis use (n=1) were the focus of the remaining articles in the sample. Mixed methods empirical research largely focuses on risks of cannabis use among Indigenous people worldwide. The small, repeating pool of senior authors represents an opportunity for capacity building. A lack of transparency about author positionality and absence of empirical studies that explore the lived experiences of Indigenous peoples and cannabis are significant gaps poised to be filled for future research and regulation.

Human cerebral spheroids undergo 4-aminopyridine-induced, activity associated changes in cellular composition and microrna expression.

Activity-induced neurogenesis has been extensively studied in rodents but the lack of ante mortem accessibility to human brain at the cellular and molecular levels limits studies of the process in humans. Using cerebral spheroids derived from human induced pluripotent stem cells (iPSCs), we investigated the effects of 4-aminopyridine (4AP) on neuronal activity and associated neurogenesis. Our studies demonstrate that 4AP increases neuronal activity in 3-month-old cerebral spheroids while increasing numbers of new neurons and decreasing the population of new glial cells. We also observed a significant decrease in the expression of miR-135a, which has previously been shown to be decreased in exercise-induced neurogenesis. Predicted targets of miR-135a include key participants in the SMAD2/3 and BDNF pathways. Together, our results suggest that iPSC-derived cerebral spheroids are an attractive model to study several aspects of activity-induced neurogenesis.

Cannabis Vapor Exposure Alters Neural Circuit Oscillatory Activity in a Neurodevelopmental Model of Schizophrenia: Exploring the Differential Impact of Cannabis Constituents.

Cannabis use is highly prevalent in patients with schizophrenia and worsens the course of the disorder. To understand how exposure to cannabis changes schizophrenia-related oscillatory disruptions, we investigated the impact of administering cannabis vapor containing either Δ9-tetrahydrocannabinol (THC) or balanced THC/cannabidiol (CBD) on oscillatory activity in the neonatal ventral hippocampal lesion (NVHL) rat model of schizophrenia. Male Sprague Dawley rats underwent lesion or sham surgeries on postnatal day 7. In adulthood, electrodes were implanted targeting the cingulate cortex (Cg), the prelimbic cortex (PrLC), the hippocampus (HIP), and the nucleus accumbens (NAc). Local field potential recordings were obtained after rats were administered either the "THC-only" cannabis vapor (8-18% THC/0% CBD) or the "Balanced THC:CBD" cannabis vapor (4-11% THC/8.5-15.5% CBD) in a cross-over design with a 2-week wash-out period between exposures. Compared to controls, NVHL rats had reduced baseline gamma power in the Cg, HIP, and NAc, and reduced HIP-Cg high-gamma coherence. THC-only vapor exposure broadly suppressed oscillatory power and coherence, even beyond the baseline reductions observed in NHVL rats. Balanced THC:CBD vapor, however, did not suppress oscillatory power and coherence, and in some instances enhanced power. For NVHL rats, THC-only vapor normalized the baseline HIP-Cg high-gamma coherence deficits. NHVL rats demonstrated a 20 ms delay in HIP theta to high-gamma phase coupling, which was not apparent in the PrLC and NAc after both exposures. In conclusion, cannabis vapor exposure has varying impacts on oscillatory activity in NVHL rats, and the relative composition of naturally occurring cannabinoids may contribute to this variability.

GSK-3ß Disrupts Neuronal Oscillatory Function to Inhibit Learning and Memory in Male Rats.

Alterations in glycogen synthase kinase-3ß (GSK-3ß) activity have been implicated in disorders of cognitive impairment, including Alzheimer's disease and schizophrenia. Cognitive dysfunction is also characterized by the dysregulation of neuronal oscillatory activity, macroscopic electrical rhythms in brain that are critical to systems communication. A direct functional relationship between GSK-3ß and neuronal oscillations has not been elucidated. Therefore, in the present study, using an adeno-associated viral vector containing a persistently active mutant form of GSK-3ß, GSK-3ß(S9A), the impact of elevated kinase activity in prefrontal cortex (PFC) or ventral hippocampus (vHIP) of rats on neuronal oscillatory activity was evaluated. GSK-3ß(S9A)-induced changes in learning and memory were also assessed and the phosphorylation status of tau protein, a substrate of GSK-3ß, examined. It was demonstrated that increasing GSK-3ß(S9A) activity in either the PFC or vHIP had similar effects on neuronal oscillatory activity, enhancing theta and/or gamma spectral power in one or both regions. Increasing PFC GSK-3ß(S9A) activity additionally suppressed high gamma PFC-vHIP coherence. These changes were accompanied by deficits in recognition memory, spatial learning, and/or reversal learning. Elevated pathogenic tau phosphorylation was also evident in regions where GSK-3ß(S9A) activity was upregulated. The neurophysiological and learning and memory deficits induced by GSK-3ß(S9A) suggest that aberrant GSK-3ß signalling may not only play an early role in cognitive decline in Alzheimer's disease but may also have a more central involvement in disorders of cognitive dysfunction through the regulation of neurophysiological network function.

Sex differences in neuronal systems function and behaviour: beyond a single diagnosis in autism spectrum disorders.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that is associated with functional brain alterations that underlie the expression of behaviour. Males are diagnosed up to four times more than females, and sex differences have been identified in memory, cognitive flexibility, verbal fluency, and social communication. Unfortunately, there exists a lack of information on the sex-dependent mechanisms of ASD, as well as biological markers to distinguish sex-specific symptoms in ASD. This can often result in a standardized diagnosis for individuals across the spectrum, despite significant differences in the various ASD subtypes. Alterations in neuronal connectivity and oscillatory activity, such as is observed in ASD, are highly coupled to behavioural states. Yet, despite the well-identified sexual dimorphisms that exist in ASD, these functional patterns have rarely been analyzed in the context of sex differences or symptomology. This review summarizes alterations in neuronal oscillatory function in ASD, discusses the age, region, symptom and sex-specific differences that are currently observed across the spectrum, and potential targets for regulating neuronal oscillatory activity in ASD. The need to identify sex-specific biomarkers, in order to facilitate specific diagnostic criteria and allow for more targeted therapeutic approaches for ASD will also be discussed.

Glycogen Synthase Kinase-3: A Focal Point for Advancing Pathogenic Inflammation in Depression.

Increasing evidence indicates that the host immune response has a monumental role in the etiology of major depressive disorder (MDD), motivating the development of the inflammatory hypothesis of depression. Central to the involvement of chronic inflammation in MDD is a wide range of signaling deficits induced by the excessive secretion of pro-inflammatory cytokines and imbalanced T cell differentiation. Such signaling deficits include the glutamatergic, cholinergic, insulin, and neurotrophin systems, which work in concert to initiate and advance the neuropathology. Fundamental to the communication between such systems is the protein kinase glycogen synthase kinase-3 (GSK-3), a multifaceted protein critically linked to the etiology of MDD and an emerging target to treat pathogenic inflammation. Here, a consolidated overview of the widespread multi-system involvement of GSK-3 in contributing to the neuropathology of MDD will be discussed, with the feed-forward mechanistic links between all major neuronal signaling pathways highlighted.

Sex Differences in Dopamine Receptors and Relevance to Neuropsychiatric Disorders.

Dopamine is an important neurotransmitter that plays a key role in neuropsychiatric illness. Sex differences in dopaminergic signaling have been acknowledged for decades and have been linked to sex-specific heterogeneity in both dopamine-related behaviours as well as in various neuropsychiatric disorders. However, the overall number of studies that have evaluated sex differences in dopamine signaling, both in health and in these disorders, is low. This review will bring together what is known regarding sex differences in innate dopamine receptor expression and function, as well as highlight the known sex-specific roles of dopamine in addiction, depression, anxiety, schizophrenia, and attention deficit hyperactivity disorder. Due to differences in prognosis, diagnosis, and symptomatology between male and female subjects in disorders that involve dopamine signaling, or in responses that utilize pharmacological interventions that target dopamine receptors, understanding the fundamental sex differences in dopamine receptors is of vital importance for the personalization of therapeutic treatment strategies.

The Antidepressant-Like and Analgesic Effects of Kratom Alkaloids are accompanied by Changes in Low Frequency Oscillations but not ΔFosB Accumulation.

Mitragyna speciosa ("kratom"), employed as a traditional medicine to improve mood and relieve pain, has shown increased use in Europe and North America. Here, the dose-dependent effects of a purified alkaloid kratom extract on neuronal oscillatory systems function, analgesia, and antidepressant-like behaviour were evaluated and kratom-induced changes in ΔFosB expression determined. Male rats were administered a low or high dose of kratom (containing 0.5 or 1 mg/kg of mitragynine, respectively) for seven days. Acute or repeated low dose kratom suppressed ventral tegmental area (VTA) theta oscillatory power whereas acute or repeated high dose kratom increased delta power, and reduced theta power, in the nucleus accumbens (NAc), prefrontal cortex (PFC), cingulate cortex (Cg) and VTA. The repeated administration of low dose kratom additionally elevated delta power in PFC, decreased theta power in NAc and PFC, and suppressed beta and low gamma power in Cg. Suppressed high gamma power in NAc and PFC was seen selectively following repeated high dose kratom. Both doses of kratom elevated NAc-PFC, VTA-NAc, and VTA-Cg coherence. Low dose kratom had antidepressant-like properties whereas both doses produced analgesia. No kratom-induced changes in ΔFosB expression were evident. These results support a role for kratom as having both antidepressant and analgesic properties that are accompanied by specific changes in neuronal circuit function. However, the absence of drug-induced changes in ΔFosB expression suggest that the drug may circumvent this cellular signaling pathway, a pathway known for its significant role in addiction.

Sex-Specific Cannabidiol- and Iloperidone-Induced Neuronal Activity Changes in an In Vitro MAM Model System of Schizophrenia.

Cortical circuit dysfunction is thought to be an underlying mechanism of schizophrenia (SZ) pathophysiology with normalization of aberrant circuit activity proposed as a biomarker for antipsychotic efficacy. Cannabidiol (CBD) shows potential as an adjunctive antipsychotic therapy; however, potential sex effects in these drug interactions remain unknown. In the present study, we sought to elucidate sex effects of CBD coadministration with the atypical antipsychotic iloperidone (ILO) on the activity of primary cortical neuron cultures derived from the rat methylazoxymethanol acetate (MAM) model used for the study of SZ. Spontaneous network activity measurements were obtained using a multielectrode array at baseline and following administration of CBD or ILO alone, or combined. At baseline, MAM male neurons displayed increased bursting activity whereas MAM female neurons exhibited no difference in bursting activity compared to sex-matched controls. CBD administered alone showed a rapid but transient increase in neuronal activity in the MAM networks, an effect more pronounced in females. Furthermore, ILO had an additive effect on CBD-induced elevations in activity in the MAM male neurons. In the MAM female neurons, CBD or ILO administration resulted in time-dependent elevations in neuronal activity, but the short-term CBD-induced increases in activity were lost when CBD and ILO were combined. Our findings indicate that CBD induces rapid increases in cortical neuronal activity, with sex-specific drug interactions upon ILO coadministration. This suggests that sex should be a consideration when implementing adjunct therapy for treatment of SZ.

Sex differences in innate and adaptive neural oscillatory patterns link resilience and susceptibility to chronic stress in rats.

Background: Major depressive disorder is a chronic illness with a higher incidence in women. Dysregulated neural oscillatory activity is an emerging mechanism thought to underlie major depressive disorder, but whether sex differences in these rhythms contribute to the development of symptoms is unknown. Methods: We exposed male and female rats to chronic unpredictable stress and characterized them as stress-resilient or stress-susceptible based on behavioural output in the forced swim test and the sucrose preference test. To identify sex-specific neural oscillatory patterns associated with stress response, we recorded local field potentials from the prefrontal cortex, cingulate cortex, nucleus accumbens and dorsal hippocampus throughout stress exposure. Results: At baseline, female stress-resilient rats innately exhibited higher theta coherence in hippocampal connections compared with stress-susceptible female rats. Following stress exposure, additional oscillatory changes manifested: stress-resilient females were characterized by increased dorsal hippocampal theta power and cortical gamma power, and stress-resilient males were characterized by a widespread increase in high gamma coherence. In stress-susceptible animals, we observed a pattern of increased delta and reduced theta power; the changes were restricted to the cingulate cortex and dorsal hippocampus in males but occurred globally in females. Finally, stress exposure was accompanied by the time-dependent recruitment of specific neural pathways, which culminated in system-wide changes that temporally coincided with the onset of depression-like behaviour. Limitations: We could not establish causality between the electrophysiological changes and behaviours with the methodology we employed. Conclusion: Sex-specific neurophysiological patterns can function as early markers for stress vulnerability and the onset of depression-like behaviours in rats.