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The effects of smoking in the human brain were explored at the molecular level in the nucleus accumbens(NAcc), a key brain region involved in tobacco addiction. Gene expression data from post-mortem NAcc were analyzed according to smoking habits: Never smokers, Former smokers and Current smokers at the time of death. The effect of smoking was determined using an ANCOVA model, controlling for potential confounders (psychiatric diagnosis, gender, age, post-mortem interval, and brain pH) followed by pair-wise post-hoc comparisons. Q-values (false discovery rate adjusted p-values) < 0.05 were used in combination with a fold change of > ±1.3 to identify the most relevant genes. The greatest number of differentially expressed genes (DEGs) were found in subjects with a recent history of smoking (Current smokers) compared to either Former or Never smokers. Only two genes were differentially expressed between Former and Never smokers, suggesting that the effects of smoking on gene expression in the brain may be transient. Ingenuity Pathway Analysis (IPA) of DEGs identified a significant over-representation of neurotransmitter system genes (glutamate, GABA) in Current smokers. IPA also revealed many genes associated with cancer in Current smokers compared to Former and Never smokers despite no known cancer in any subjects. Genes associated with neoplasms, glioblastoma, gliomas and tumor regulations are among the top 10 transcripts.Our findings show that active smokers have a significant increase in cancer-related genes and alterations in glutamate and GABA neurotransmitter systems in the NAcc. To our knowledge this is the first study to identify cancer-related genes in the NAcc in Current smokers who have no evidence of cancer.

Brodmann Area 10 (BA10) is the largest cytoarchitectonic region of the human cortex, performing complex integrative functions. BA10 undergoes intensive adolescent grey matter pruning around the average age of onset for Bipolar disorder (BP) and Schizophrenia (SCHIZ), and its dysfunction is likely to underly aspects of their shared symptomology. In this study, we investigated the role of BA10 neurotransmission-related gene expression in BP and SCHIZ. We performed qPCR to measure the expression of 115 neurotransmission-related targets in control, BP, and SCHIZ post-mortem samples (n=72). We chose this method for its high sensitivity to detect low-level expression. We then bolstered our findings by performing a meta-analysis of publicly-released BA10 microarray data (n=101) and identified sources of convergence with our qPCR results. To improve interpretation, we compiled an unusually large database of clinical metadata for our samples. We used this data to explore the relationship between BA10 gene expression, therapeutics, substances of abuse, and symptom profiles, and validated these findings with publicly-available datasets. Using these convergent sources of evidence, we identified 20 neurotransmission-related genes that were differentially expressed in BP and SCHIZ in BA10. These results included a large diagnosis-related decrease in two important therapeutic targets with low-levels of expression, HTR2B and DRD4, as well as other findings related to dopaminergic, GABA-ergic and astrocytic function. We also observed that therapeutics may produce differential expression that opposes the effects of diagnosis. In contrast, substances of abuse showed similar effects on BA10 gene expression as BP and SCHIZ, potentially amplifying diagnosis-related dysregulation.

New antidepressant treatments are needed that are effective, rapid acting, safe, and tolerable. Intermittent theta-burst stimulation (iTBS) is a noninvasive brain stimulation treatment that has been approved by the U.S. Food and Drug Administration for treatment-resistant depression. Recent methodological advances suggest that the current iTBS protocol might be improved through 1) treating patients with multiple sessions per day at optimally spaced intervals, 2) applying a higher overall pulse dose of stimulation, and 3) precision targeting of the left dorsolateral prefrontal cortex (DLPFC) to subgenual anterior cingulate cortex (sgACC) circuit. The authors examined the feasibility, tolerability, and preliminary efficacy of Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT), an accelerated, high-dose resting-state functional connectivity MRI (fcMRI)-guided iTBS protocol for treatment-resistant depression.Twenty-two participants with treatment-resistant depression received open-label SAINT. fcMRI was used to individually target the region of the left DLPFC most anticorrelated with sgACC in each participant. Fifty iTBS sessions (1,800 pulses per session, 50-minute intersession interval) were delivered as 10 daily sessions over 5 consecutive days at 90% resting motor threshold (adjusted for cortical depth). Neuropsychological testing was conducted before and after SAINT.One participant withdrew, leaving a sample size of 21. Nineteen of 21 participants (90.5%) met remission criteria (defined as a score11 on the Montgomery-Åsberg Depression Rating Scale). In the intent-to-treat analysis, 19 of 22 participants (86.4%) met remission criteria. Neuropsychological testing demonstrated no negative cognitive side effects.SAINT, an accelerated, high-dose, iTBS protocol with fcMRI-guided targeting, was well tolerated and safe. Double-blinded sham-controlled trials are needed to confirm the remission rate observed in this initial study.

Thermoregulation in animals is an adaptation made to live through hot summers and cold winters. Big game animals such as: deer, elk, and pronghorn antelope have the adaptation more commonly known as a summer coat and a winter coat. We measured and compared an animal's winter coat and summer coat using a scanning electron microscope to show why an animal can survive outdoor temperatures. We used a scanning electron microscope to identify the different topography of the individual hair and focused on the thermodynamics of each individual hair.

Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analyzing the whole-exomes of 24,248 cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in ten genes as conferring substantial risk for schizophrenia (odds ratios 3 – 50, P < 2.14 × 10(−6)), and 32 genes at a FDR < 5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure, and function of the synapse. The associations of NMDA receptor subunit GRIN2A and AMPA receptor subunit GRIA3 provide support for the dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We observe an overlap of rare variant risk between schizophrenia, autism spectrum disorders (ASD)(1), epilepsy and severe neurodevelopmental disorders (DD/ID)(2), though in some shared genes different mutation types are implicated. Most genes described here however are not implicated in neurodevelopment and we demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk(3), suggesting that common and rare genetic risk factors at least partially converge on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, implying that more risk genes await discovery using this approach.

Mitochondrial dysfunction is a neurobiological phenomenon implicated in the pathophysiology of schizophrenia and bipolar disorder that can synergistically affect synaptic neurotransmission. We hypothesized that schizophrenia and bipolar disorder share molecular alterations at the mitochondrial and synaptic level: mtDNA copy number (CN), mtDNA common deletion (CD), mtDNA total deletion, complex I activity, synapse number, and synaptic mitochondria number. These mitochondrial parameters were studied in dorsolateral prefrontal cortex (DLPFC), superior temporal gyrus (STG), primary visual cortex (V1), and nucleus accumbens (NAc) of 44 controls (CON), 27 schizophrenia (SZ), and 26 bipolar disorder (BD) subjects. The results showed- (i) the mtDNA CN is significantly higher in DLPFC of both SZ and BD, decreased in the STG of BD, and unaltered in V1 and NAc of both SZ and BD; (ii) the mtDNA CD is significantly higher in DLPFC of BD while unaltered in STG, V1 and NAc of both SZ and BD; (iii) The total deletion burden is significantly higher in DLPFC in both SZ and BD while unaltered in STG, V1, and NAc of SZ and BD; (iv) Complex I activity is significantly lower in DLPFC of both SZ and BD with no alteration in STG, V1 and NAc. (v) The number of synapses is decreased in DLPFC of both SZ and BD, while the synaptic mitochondria number was significantly lower in female SZ and female BD compared to female controls. Overall, these findings will pave the way to better understand the pathophysiology of schizophrenia and bipolar disorder for therapeutic interventions.