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 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.

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.

Glycogen synthase kinase-3: The missing link to aberrant circuit function in disorders of cognitive dysfunction?

Elevated GSK-3 activity has been implicated in cognitive dysfunction associated with various disorders including Alzheimer's disease, schizophrenia, type 2 diabetes, traumatic brain injury, major depressive disorder and bipolar disorder. Further, aberrant neural oscillatory activity in, and between, cortical regions and the hippocampus is consistently present within these same cognitive disorders. In this review, we will put forth the idea that increased GSK-3 activity serves as a pathological convergence point across cognitive disorders, inducing similar consequent impacts on downstream signaling mechanisms implicated in the maintenance of processes critical to brain systems communication and normal cognitive functioning. In this regard we suggest that increased activation of GSK-3 and neuronal oscillatory dysfunction are early pathological changes that may be functionally linked. Mechanistic commonalities between these disorders of cognitive dysfunction will be discussed and potential downstream targets of GSK-3 that may contribute to neuronal oscillatory dysfunction identified.

The atypical dopamine receptor agonist SKF 83959 enhances hippocampal and prefrontal cortical neuronal network activity in a rat model of cognitive dysfunction.

Deficits in neuronal network synchrony in hippocampus and prefrontal cortex have been widely demonstrated in disorders of cognitive dysfunction, including schizophrenia and Alzheimer's disease. The atypical dopamine agonist SKF 83959 has been shown to increase brain-derived neurotrophic factor signalling and suppress activity of glycogen synthase kinase-3 in PFC, two processes important to learning and memory. The purpose of this study was to therefore evaluate the impact of SKF 83959 on oscillatory deficits in methylazoxymethanol acetate (MAM) rat model of schizophrenia. To achieve this, local field potentials were recorded simultaneously from the hippocampus and prefrontal cortex of anesthetized rats at 15 and 90 min following both acute and repeated administration of SKF 83959 (0.4 mg/kg). In MAM rats, but not controls, repeated SKF 83959 treatment increased signal amplitude in hippocampus and enhanced the spectral power of low frequency delta and theta oscillations in this region. In PFC, SKF 83959 increased delta, theta and gamma spectral power. Increased HIP-PFC theta coherence was also evident following acute and repeated SKF 83959. In apparent contradiction to these oscillatory effects, in MAM rats, SKF 83959 inhibited spatial learning and induced a significant increase in thigmotactic behaviour. These findings have uncovered a previously unknown role for SKF 83959 in the positive regulation of hippocampal-prefrontal cortical oscillatory network activity. As SKF 83959 is known to have affinity for a number of receptors, delineating the receptor mechanisms that mediate the positive drug effects on neuronal oscillations could have significant future implications in disorders associated with cognitive dysfunction.

A peptide targeting an interaction interface disrupts the dopamine D1-D2 receptor heteromer to block signaling and function in vitro and in vivo: effective selective antagonism.

Although the dopamine D1-D2 receptor heteromer has emerging physiological relevance and a postulated role in different neuropsychiatric disorders, such as drug addiction, depression, and schizophrenia, there is a need for pharmacological tools that selectively target such receptor complexes in order to analyze their biological and pathophysiological functions. Since no selective antagonists for the D1-D2 heteromer are available, serial deletions and point mutations were used to precisely identify the amino acids involved in an interaction interface between the receptors, residing within the carboxyl tail of the D1 receptor that interacted with the D2 receptor to form the D1-D2 receptor heteromer. It was determined that D1 receptor carboxyl tail residues (404)Glu and (405)Glu were critical in mediating the interaction with the D2 receptor. Isolated mutation of these residues in the D1 receptor resulted in the loss of agonist activation of the calcium signaling pathway mediated through the D1-D2 receptor heteromer. The physical interaction between the D1 and D2 receptor could be disrupted, as shown by coimmunoprecipitation and BRET analysis, by a small peptide generated from the D1 receptor sequence that contained these amino acids, leading to a switch in G-protein affinities and loss of calcium signaling, resulting in the inhibition of D1-D2 heteromer function. The use of the D1-D2 heteromer-disrupting peptide in vivo revealed a pathophysiological role for the D1-D2 heteromer in the modulation of behavioral despair. This peptide may represent a novel pharmacological tool with potential therapeutic benefits in depression treatment.

Dopamine D1-D2 receptor heteromer regulates signaling cascades involved in addiction: potential relevance to adolescent drug susceptibility.

Adolescence is a developmental period that has been associated with heightened sensitivity to psychostimulant-induced reward, thus placing adolescents at increased risk to develop drug addiction. Although alterations in dopamine-induced synaptic plasticity are perhaps the most critical factor in mediating addiction processes, developmental differences in the cell signaling mechanisms that contribute to synaptic plasticity, and their contribution to adolescent reward sensitivity, has been grossly understudied. The most abundant dopamine receptors, the D1 and D2 receptors, as well as the dopamine D1-D2 receptor heteromer, exhibit age-dependent and brain region-specific changes in their expression and function and are responsible for regulating cell signaling pathways known to significantly contribute to the neurobiological mechanisms underlying addiction. The D1-D2 receptor heteromer, for instance, has been associated with calcium calmodulin kinase IIα, brain-derived neurotrophic factor and glycogen synthase kinase 3 (GSK-3) signaling, three proteins highly implicated in the regulation of glutamate transmission and synaptic plasticity and which regulate addiction to amphetamine, opioids and cocaine. Therefore, in this review the importance of these signaling proteins as potential mediators of addiction susceptibility in adolescence will be highlighted, and the therapeutic potential of the D1-D2 receptor heteromer in addiction will be discussed. It is the overall goal of this review to draw attention to the research gap in dopamine-induced cell signaling in the adolescent brain--knowledge that would provide much-needed insights into adolescent addiction vulnerability.

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.

Enhanced brain-derived neurotrophic factor signaling in the nucleus accumbens of juvenile rats.

Brain-derived neurotrophic factor (BDNF) signaling through its receptor, tropomyosin receptor kinase B (TrkB), plays a critical role in neural plasticity and its dysregulation in striatum and prefrontal cortex (PFC) has been implicated in the etiology of mental health disorders such schizophrenia and drug addiction. In the present study, we characterized age-dependent differences in BDNF signaling and TrkB expression within the nucleus accumbens (NAc), caudate putamen (CP) and PFC in rats and determined the effects of administration of the dopamine agonist, SKF 83959, which activates the Gq-coupled dopamine receptors, the dopamine D5 receptor and the D1-D2 receptor heteromer. As proBDNF binds with high affinity to the p75 neurotrophin receptor (p75NTR), expression levels of these proteins were also assessed. The present findings showed that juvenile rats (aged 26-28 days) exhibited significantly elevated basal BDNF expression and activation of full-length TrkB (TrkBfull) in NAc compared to their adult counterparts, as evidenced by increased TrkBfull phosphorylation. These changes were concomitant with an increase in the relative expression of TrkBfull compared to the truncated isoform, TrkB.T1, in NAc and CP. Conversely, in PFC the basal expression of BDNF in juvenile rats was significantly lower than in adult rats with an elevated relative expression of TrkBfull. Acute administration of SKF 83959 to juvenile rats abolished the age-dependent differences in BDNF expression in NAc and PFC, and in the relative expression of TrkBfull in NAc and CP. Together these findings indicate that the expression and/or signaling of BDNF and TrkB in striatum and PFC of juvenile rats is fundamentally different from that of adult rats, a finding that may have implications in neuropsychiatric disorders that exhibit age-dependent susceptibility such as schizophrenia and drug addiction.

A physiological role for the dopamine D5 receptor as a regulator of BDNF and Akt signalling in rodent prefrontal cortex.

The dopamine D5 receptor (D5R) exhibits a wide distribution in prefrontal cortex (PFC) but its role in this region has not yet been elucidated. In the present study, we identified a novel physiological function for the D(5)R as a regulator of brain-derived neurotrophic factor (BDNF) and Akt signalling in PFC. Specifically, acute activation of the D(5)R by the dopamine agonist SKF 83959 enhanced BDNF expression and signalling through its receptor, tropomyosin receptor kinase B (TrkB), in rats and in mice gene-deleted for the D1 receptor but not the D(5)R. These changes were concomitant with increased expression of GAD67, a protein whose down-regulation has been implicated in the aetiology of schizophrenia. Furthermore, D(5)R activation increased phosphorylation of Akt at the Ser(473) site, consequently decreasing the activity of its substrate GSK-3ß. These findings could have wide-reaching implications given evidence showing activation of these pathways in PFC has therapeutic effects in neuropsychiatric disorders such as drug addiction, schizophrenia and depression.

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.

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.

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.

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.

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.

Calcium signaling cascade links dopamine D1-D2 receptor heteromer to striatal BDNF production and neuronal growth.

Although the perturbation of either the dopaminergic system or brain-derived neurotrophic factor (BDNF) levels has been linked to important neurological and neuropsychiatric disorders, there is no known signaling pathway linking these two major players. We found that the exclusive stimulation of the dopamine D1-D2 receptor heteromer, which we identified in striatal neurons and adult rat brain by using confocal FRET, led to the activation of a signaling cascade that links dopamine signaling to BDNF production and neuronal growth through a cascade of four steps: (i) mobilization of intracellular calcium through Gq, phospholipase C, and inositol trisphosphate, (ii) rapid activation of cytosolic and nuclear calcium/calmodulin-dependent kinase IIalpha, (iii) increased BDNF expression, and (iv) accelerated morphological maturation and differentiation of striatal neurons, marked by increased microtubule-associated protein 2 production. These effects, although robust in striatal neurons from D5(-/-) mice, were absent in neurons from D1(-/-) mice. We also demonstrated that this signaling cascade was activated in adult rat brain, although with regional specificity, being largely limited to the nucleus accumbens. This dopaminergic pathway regulating neuronal growth and maturation through BDNF may have considerable significance in disorders such as drug addiction, schizophrenia, and depression.

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.

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.