The epigenetic landscape is vulnerable to diets. Here, we investigated the influence of different polyunsaturated fatty acids (PUFA) dietary supplements on rodents' nervous system development and functions and potential consequences to neurodegenerative disorders. Our previous nutrigenomics study showed significant impact of high n-3 PUFA-enriched diet (ERD) on synaptogenesis and various neuromodulators. The present study introduced a second equicaloric diet with n-6 PUFA balanced by n-3 PUFA (BLD). The typical lab diet with high n-6 PUFA was the baseline. Transcriptomic and epigenetic investigations, namely microRNA (miRNA) and DNA methylation assays, were carried out on the hemibrains of the C57BL/6j mice fed on any of these three diets from their neonatal age to midlife. Integrating the multiomics data, we focused on the genes encoding both hypermethylated CpG islands and suppressed transcripts. In addition, miRNA:mRNA pairs were screened to identify those overexpressed miRNAs that reduced transcriptional expressions. The majority of miRNAs overexpressed by BLD are associated with Alzheimer's and schizophrenia. BLD implicated long-term potentiation, memory, cognition and learning, primarily via hypermethylation of those genes that enrich the calcium-releasing neurotransmitters. ERD caused hypermethylation of those genes that enrich cytoskeletal development networks and promote the formation of neuronal precursors. We drew the present observations in light of our limited knowledge regarding the epigenetic influences on biofunctions. A more comprehensive study is essential to understand the broad influences of dietary supplements and to suggest optimal dietary solutions for neurological disorders.

Treatment-resistant schizophrenia (TRS), the persistence of positive symptoms despite ≥2 trials of adequate dose and duration of antipsychotic medication with documented adherence, is a serious clinical problem with heterogeneous presentations. TRS can vary in its onset (at the first episode of psychosis or upon relapse), in its severity, and in the response to subsequent therapeutic interventions (i.e., clozapine, electroconvulsive therapy). The heterogeneity of TRS indicates that the underlying neurobiology of TRS may differ not only from treatment-responsive schizophrenia but also among patients with TRS. Several hypotheses have been proposed for the neurobiological mechanisms underlying TRS, including dopamine supersensitivity, hyperdopaminergic and normodopaminergic subtypes, glutamate dysregulation, inflammation and oxidative stress, and serotonin dysregulation. Research supporting these hypotheses is limited in part by variations in the criteria used to define TRS, as well as by the biological and clinical heterogeneity of TRS. Clinical trial designs for new treatments should be informed by this heterogeneity, and further clinical research is needed to more clearly understand the underlying neurobiology of TRS and to optimize treatment for patients with TRS.

We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n = 35,584 total samples, 11,986 with ASD). Using an enhanced analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained to have severe neurodevelopmental delay, whereas 53 show higher frequencies in individuals ascertained to have ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In cells from the human cortex, expression of risk genes is enriched in excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory-inhibitory imbalance underlying ASD.

Intense stress, especially traumatic stress, can trigger disabling responses and in some cases even lead to the development of posttraumatic stress disorder (PTSD). PTSD is heterogeneous, accompanied by a range of distress symptoms and treatment-resistant disorders that may be associated with a number of other psychopathologies. PTSD is a very heterogeneous disorder with different subtypes that depend on, among other factors, the type of stressor that provokes it. However, the neurobiological mechanisms are poorly understood. The study of early stress responses may hint at the way PTSD develops and improve the understanding of the neurobiological mechanisms involved in its onset, opening the opportunity for possible preventive treatments. Proteomics is a promising strategy for characterizing these early mechanisms underlying the development of PTSD. The aim of the work was to understand how exposure to acute and intense stress using water immersion restraint stress (WIRS), which could be reminiscent of natural disaster, may induce several PTSD-associated symptoms and changes in the hippocampal proteomic profile. The results showed that exposure to WIRS induced behavioural symptoms and corticosterone levels reminiscent of PTSD. Moreover, the expression profiles of hippocampal proteins at 1 h and 24 h after stress were deregulated in favour of increased inflammation and reduced neuroplasticity, which was validated by histological studies and cytokine determination. Taken together, these results suggest that neuroplastic and inflammatory dysregulation may be a therapeutic target for the treatment of post-traumatic stress disorders.

Mutations in four genes have been identified in familial hemiplegic migraine (FHM), from which CACNA1A (FHM type 1) and SCN1A (FHM type 3) code for neuronal voltage-gated calcium or sodium channels, respectively, while ATP1A2 (FHM type 2) encodes the α2 isoform of the Na(+),K(+)-ATPase's catalytic subunit, thus classifying FHM primarily as an ion channel/ion transporter pathology. FHM type 4 is attributed to mutations in the PRRT2 gene, which encodes a proline-rich transmembrane protein of as yet unknown function. The Na(+),K(+)-ATPase maintains the physiological gradients for Na(+) and K(+) ions and is, therefore, critical for the activity of ion channels and transporters involved neuronal excitability, neurotransmitter uptake or Ca(2+) signaling. Strikingly diverse functional abnormalities have been identified for disease-linked ATP1A2 mutations which frequently lead to changes in the enzyme's voltage-dependent properties, kinetics, or apparent cation affinities, but some mutations are truly deleterious for enzyme function and thus cause full haploinsufficiency. Here, we summarize structural and functional data about the Na(+),K(+)-ATPase available to date and an overview is provided about the particular properties of the α2 isoform that explain its physiological relevance in electrically excitable tissues. In addition, current concepts about the neurobiology of migraine, the correlations between primary brain dysfunction and mechanisms of headache pain generation are described, together with insights gained recently from modeling approaches in computational neuroscience. Then, a survey is given about ATP1A2 mutations implicated in migraine cases as documented in the literature with focus on mutations that were described to completely destroy enzyme function, or lead to misfolded or mistargeted protein in particular model cell lines. We also discuss whether or not there are correlations between these most severe mutational effects and clinical phenotypes. Finally, perspectives for future research on the implications of Na(+),K(+)-ATPase mutations in human pathologies are presented.

Recent large genome-wide association studies have identified multiple confident risk loci linked to addiction-associated behavioral traits. Most genetic variants linked to addiction-associated traits lie in noncoding regions of the genome, likely disrupting cis-regulatory element (CRE) function. CREs tend to be highly cell type-specific and may contribute to the functional development of the neural circuits underlying addiction. Yet, a systematic approach for predicting the impact of risk variants on the CREs of specific cell populations is lacking. To dissect the cell types and brain regions underlying addiction-associated traits, we applied stratified linkage disequilibrium score regression to compare genome-wide association studies to genomic regions collected from human and mouse assays for open chromatin, which is associated with CRE activity. We found enrichment of addiction-associated variants in putative CREs marked by open chromatin in neuronal (NeuN+) nuclei collected from multiple prefrontal cortical areas and striatal regions known to play major roles in reward and addiction. To further dissect the cell type-specific basis of addiction-associated traits, we also identified enrichments in human orthologs of open chromatin regions of female and male mouse neuronal subtypes: cortical excitatory, D1, D2, and PV. Last, we developed machine learning models to predict mouse cell type-specific open chromatin, enabling us to further categorize human NeuN+ open chromatin regions into cortical excitatory or striatal D1 and D2 neurons and predict the functional impact of addiction-associated genetic variants. Our results suggest that different neuronal subtypes within the reward system play distinct roles in the variety of traits that contribute to addiction.SIGNIFICANCE STATEMENT We combine statistical genetic and machine learning techniques to find that the predisposition to for nicotine, alcohol, and cannabis use behaviors can be partially explained by genetic variants in conserved regulatory elements within specific brain regions and neuronal subtypes of the reward system. Our computational framework can flexibly integrate open chromatin data across species to screen for putative causal variants in a cell type- and tissue-specific manner for numerous complex traits.

Healthy people sometimes report experiences and beliefs that are strikingly similar to the symptoms of psychosis in their bizarreness and the apparent lack of evidence supporting them. An important question is whether this represents merely a superficial resemblance or whether there is a genuine and deep similarity indicating, as some have suggested, a continuum between odd but healthy beliefs and the symptoms of psychotic illness. We sought to shed light on this question by determining whether the neural marker for prediction error - previously shown to be altered in early psychosis--is comparably altered in healthy individuals reporting schizotypal experiences and beliefs. We showed that non-clinical schizotypal experiences were significantly correlated with aberrant frontal and striatal prediction error signal. This correlation related to the distress associated with the beliefs. Given our previous observations that patients with first episode psychosis show altered neural responses to prediction error and that this alteration, in turn, relates to the severity of their delusional ideation, our results provide novel evidence in support of the view that schizotypy relates to psychosis at more than just a superficial descriptive level. However, the picture is a complex one in which the experiences, though associated with altered striatal responding, may provoke distress but may nonetheless be explained away, while an additional alteration in frontal cortical responding may allow the beliefs to become more delusion-like: intrusive and distressing.

The migraine premonitory phase is characterized in part by increased thirst, urination and yawning. Imaging studies show that the hypothalamus is activated in the premonitory phase. Stress is a well know migraine initiation factor which was demonstrated to engage dynorphin/kappa opioid receptors (KOR) signaling in several brain regions, including the hypothalamus. This study proposes the exploration of the possible link between hypothalamic KOR and migraine premonitory symptoms in rodent models.

Electronic nicotine delivery systems (ENDS) are distinctly different from combustible cigarettes because of the availability of flavor options. Subjective measures have been used to demonstrate that adults and adolescents prefer flavors for various reasons; (1) they are pleasing and (2) they mask the harshness of nicotine. Despite this, there have been few investigations into the molecular interactions that connect chemical flavorants to smoking or vaping-related behaviors. Here, we investigated the effects of three chemical flavorants (hexyl acetate, ethyl acetate, and methylbutyl acetate) that are found in green apple (GA) ENDS e-liquids but are also found in other flavor categories. We used a translationally relevant vapor self-administration mouse model and observed that adult male and female mice self-administered GA flavorants in the absence of nicotine. Using α4-mCherryα6-GFP nicotinic acetylcholine receptor (nAChR) mice, we observed that mice exposed to GA flavorants exhibited a sex-specific increase (upregulation) of nAChRs that was also brain-region specific. Electrophysiology revealed that mice exposed to GA flavorants exhibited enhanced firing of ventral tegmental area dopamine neurons. Fast-scan cyclic voltammetry revealed that electrically stimulated dopamine release in the nucleus accumbens core is increased in mice that are exposed to GA flavorants. These effects were similarly observed in the medial habenula. Overall, these findings demonstrate that ENDS flavors alone change neurobiology and may promote vaping-dependent behaviors in the absence of nicotine. Furthermore, the flavorant-induced changes in neurobiology parallel those caused by nicotine, which highlights the fact that nonmenthol flavorants may contribute to or enhance nicotine reward and reinforcement.SIGNIFICANCE STATEMENT The impact of flavors on vaping is a hotly debated topic; however, few investigations have examined this in a model that is relevant to vaping. Although a full understanding of the exact mechanism remains undetermined, our observations reveal that chemical flavorants in the absence of nicotine alter brain circuits relevant to vaping-related behavior. The fact that the flavorants investigated here exist in multiple flavor categories of vaping products highlights the fact that a multitude of flavored vaping products may pose a risk toward vaping-dependent behaviors even without the impact of nicotine. Furthermore, as the neurobiological changes have an impact on neurons of the reward system, there exists the possibility that nonmenthol flavorants may enhance nicotine reward and reinforcement.

Maternal inflammation during pregnancy can elevate the risk of neurodegenerative disorders in offspring. However, how it affects age-related impairments of spatial learning and memory and changes in the neurobiological indictors in the offspring in later adulthood is still elusive. In this study, the CD-1 mice with maternal gestational inflammation due to receiving lipopolysaccharide (LPS, i.p. 50 or 25μg/kg) were divided into 3-, 12-, 18-, and 22-month-old groups. The spatial learning and memory were evaluated using a six-radial arm water maze and the levels of presynaptic proteins (synaptotagmin-1 and syntaxin-1) and histone acetylation (H3K9ac and H4K8ac) in the dorsal hippocampus were detected using the immunohistochemical method. The results indicated that there were significant age-related impairments of spatial learning and memory, decreased levels of H4K8ac, H3K9ac, and syntaxin-1, and increased levels of synaptotagmin-1 in the offspring mice from 12 months old to 22 months old compared to the same-age controls. Maternal LPS treatment significantly exacerbated the offspring impairments of spatial learning and memory, the reduction of H3K9ac, H4K8ac, and syntaxin-1, and the increment of synaptotagmin-1 from 12 months old to 22 months old compared to the same-age control groups. The changes in the neurobiological indicators significantly correlated with the impairments of spatial learning and memory. Furthermore, this correlation, besides the age and LPS-treatment effects, also showed a dose-dependent effect. Our results suggest that maternal inflammation during pregnancy could exacerbate age-related impairments of spatial learning and memory, and neurobiochemical indicators in the offspring CD-1 mice from midlife to senectitude.

Classroom undergraduate research experiences (CUREs) provide students access to the measurable benefits of undergraduate research experiences (UREs). Herein, we describe the implementation and assessment of a novel model for cohesive CUREs focused on central research themes involving faculty research collaboration across departments. Specifically, we implemented three collaborative CUREs spanning chemical biology, biochemistry, and neurobiology that incorporated faculty members' research interests and revolved around the central theme of visualizing biological processes like Mycobacterium tuberculosis enzyme activity and neural signaling using fluorescent molecules. Each CURE laboratory involved multiple experimental phases and culminated in novel, open-ended, and reiterative student-driven research projects. Course assessments showed CURE participation increased students' experimental design skills, attitudes and confidence about research, perceived understanding of the scientific process, and interest in science, technology, engineering, and mathematics disciplines. More than 75% of CURE students also engaged in independent scientific research projects, and faculty CURE contributors saw substantial increases in research productivity, including increased undergraduate student involvement and academic outputs. Our collaborative CUREs demonstrate the advantages of multicourse CUREs for achieving increased faculty research productivity and traditional CURE-associated student learning and attitude gains. Our collaborative CURE design represents a novel CURE model for ongoing laboratory reform that benefits both faculty and students.

Our earlier work generated a powerful platform technology of polymeric scaffolding of stem cells to investigate and treat the injured or diseased central nervous system. However, the reciprocal sequelae between biophysical properties of the polymer and responses of the stem cell have not been examined in situ in lesioned spinal cords. We postulated that implantable synthetic scaffolds, acting through physical features, might affect donor cell behavior and host tissue remodeling. To test this hypothesis, poly(d,l-lactic-co-glycolic acid) (PLGA) in either low/soft or high/hard rigidity was fabricated for carrying adult human bone marrow mesenchymal stromal stem cells (hMSCs). The construct was transplanted into the epicenter of a rat model of acute T9-10 segmental hemisection to evaluate the effect of PLGA rigidity on the therapeutic potential and fate of hMSCs for neural repair. Compared to controls, only treatment with soft PLGA-scaffolded hMSCs significantly improved sensorimotor function via activation of recovery neurobiology mechanisms. The main benefits included inhibiting neuroinflammation and enhancing tissue protection. Also detected in the treated lesion region were expressions of neurotrophic and anti-inflammatory factors together with proliferation of endogenous neural stem cells, impacts likely derived from hMSCs' functional multipotency maintained by soft PLGA-scaffolding. Conversely, hard rigidity PLGA activated mechanotransduction and mesoderm lineage differentiation of hMSCs that ectopically produced bone, cartilage and muscle markers in neural parenchyma. The findings collectively suggested that the physical texture of polymeric scaffolds should be tailored for sustaining the stemness of hMSCs to constructively interact with the spinal cord for functional restoration.

Aging is a major risk factor for Alzheimer's disease (AD), the most common cause of dementia worldwide. TDP-43 proteinopathy is reported to be associated with AD pathology is almost 50% of cases. Our exploratory study examined near end-stage (28 months old) mice selectively driving expression of human TDP-43 in the hippocampus and cortex in an APP/PSEN1 background. We hypothesized that hippocampal neuropathology caused by β-amyloidosis with TDP-43 proteinopathy induced in this model, resembling the pathology seen in AD cases, manifest with changes in resting state functional connectivity. In vivo magnetic resonance imaging and post-mortem histology were performed on four genotypes: wild type, APP/PSEN1, Camk2a/TDP-43, and Camk2a/TDP-43/APP/PSEN1. Our results revealed loss of functional coupling in hippocampus and amygdala that was associated with severe neuronal loss in dentate gyrus of Camk2a/TDP-43/APP/PSEN1 mice compared to APP/PSEN1 and wild type mice. The loss of cells was accompanied by high background of β-amyloid plaques with sparse phosphorylated TDP-43 pathology. The survival rate was also reduced in Camk2a/TDP-43/APP/PSEN1 mice compared to other groups. This end-of-life study provides exploratory data to reach a better understanding of the role of TDP-43 hippocampal neuropathology in diseases with co-pathologies of TDP-43 proteinopathy and β-amyloidosis such as AD and limbic predominant age-related TDP-43 encephalopathy (LATE).

Attention-deficit/hyperactivity disorder (ADHD) is a common childhood-onset neurodevelopmental disorder characterised by persistent inattention, hyperactivity and impulsivity. Moreover, ADHD is commonly associated with other comorbid diseases (depression, anxiety, bipolar disorder, etc.). The ADHD symptomatology interferes with subject function and development. The treatment of ADHD requires a multidisciplinary approach based on a combination of non-pharmacological and pharmacological treatments with the aim of ameliorating the symptomatology; among first-line pharmacological treatments are stimulants [such as methylphenidate (MPH) and lisdexamfetamine dimesylate (LDX)]. In this review we explored recent ADHD- and stimulants-related literature, with the aim of compiling available descriptions of molecular pathways altered in ADHD, and molecular mechanisms of current first-line stimulants MPH and LDX. While conducting the narrative review, we applied structured search strategies covering PubMed/MEDLINE database and performed handsearching of reference lists on the results of those searches. The aetiology and pathophysiology of ADHD are incompletely understood; both genetic and environmental factors have been associated with the disorder and its grade of burden, and also the relationship between the molecular mechanisms of pharmacological treatments and their clinical implications. The lack of comprehensive understanding of the underlying molecular pathology makes both the diagnosis and treatment difficult. Few published studies evaluating molecular data on the mechanism of action (MoA) of MPH and LDX on ADHD are available and most of them are based on animal models. Further studies are necessary to improve the knowledge of ADHD pathophysiology and how the MoAs of MPH and LDX differentially modulate ADHD pathophysiology and control ADHD symptomatology.

Alzheimer's disease (AD) is characterized by brain plaques, tangles, and cognitive impairment. AD is one of the most common age-related dementias in humans. Progress in characterizing AD and other age-related disorders is hindered by a perceived dearth of animal models that naturally reproduce diseases observed in humans. Mice and nonhuman primates are model systems used to understand human diseases. Still, these model systems lack many of the biological characteristics of Alzheimer-like diseases (e.g., plaques, tangles) as they grow older. In contrast, companion animal models (cats and dogs) age in ways that resemble humans. Both companion animal models and humans show evidence of brain atrophy, plaques, and tangles, as well as cognitive decline with age. We embrace a One Health perspective, which recognizes that the health of humans is connected to those of animals, and we illustrate how such a perspective can work synergistically to enhance human and animal health. A comparative biology perspective is ideally suited to integrate insights across veterinary and human medical disciplines and solve long-standing problems in aging.

Using functional magnetic resonance imaging (fMRI) we investigated whether a culturally defined context modulates the neurocognitive processing of artworks. We presented subjects with paintings from the Museum of Modern Art (MoMA) in New York, and labeled them as being either from the MoMA or from an adult education center. Irrespective of aesthetic appreciation, we found higher neural activation in the left precuneus, superior and inferior parietal cortex for the MoMA condition compared to the control label condition. When taking the aesthetic preference for a painting into account, the MoMA condition elicited higher involvement of right precuneus, bilateral anterior cingulate cortex (ACC), and temporoparietal junction (TPJ). Our findings indicate that mental frames, in particular labels of social value, modulate both cognitive and affective aspects of sensory processing.

Strongly polyphenic social insects provide excellent models to examine the neurobiological basis of division of labor. Turtle ants, Cephalotes varians, have distinct minor worker, soldier, and reproductive (gyne/queen) morphologies associated with their behavioral profiles: small-bodied task-generalist minors lack the phragmotic shield-shaped heads of soldiers, which are specialized to block and guard the nest entrance. Gynes found new colonies and during early stages of colony growth overlap behaviorally with soldiers. Here we describe patterns of brain structure and synaptic organization associated with division of labor in C. varians minor workers, soldiers, and gynes. We quantified brain volumes, determined scaling relationships among brain regions, and quantified the density and size of microglomeruli, synaptic complexes in the mushroom body calyxes important to higher-order processing abilities that may underpin behavioral performance. We found that brain volume was significantly larger in gynes; minor workers and soldiers had similar brain sizes. Consistent with their larger behavioral repertoire, minors had disproportionately larger mushroom bodies than soldiers and gynes. Soldiers and gynes had larger optic lobes, which may be important for flight and navigation in gynes, but serve different functions in soldiers. Microglomeruli were larger and less dense in minor workers; soldiers and gynes did not differ. Correspondence in brain structure despite differences in soldiers and gyne behavior may reflect developmental integration, suggesting that neurobiological metrics not only advance our understanding of brain evolution in social insects, but may also help resolve questions of the origin of novel castes.

The performance enhancing (ergogenic) placebo effect is elicited by an inert treatment and caused by positive affective appraisal of effort perception. Frontal alpha asymmetry (FAA) is a neurobiological correlate of positive affect. This study investigates, whether receiving an ergogenic placebo increases FAA and whether scores on the behavioral inhibition and activation system (BIS/BAS) scales affect this increase in FAA. Nineteen competitive male cyclists (37.26 ± 9.82 years) performed two maximum effort time trials. The first served as baseline for the second intervention time trial, where athletes received a placebo ergogenic aid or no treatment. We recorded FAA using EEG throughout all time trials and assessed BIS/BAS by questionnaire. There was a significant difference in change from baseline to intervention time trial in FAA during cycling in response to the placebo ergogenic aid compared to the control group. BIS, the BAS subscale Drive and the BAS-BIS difference score significantly co-varied with the change in FAA from baseline to intervention time trial in response to the placebo ergogenic aid. Administering a placebo ergogenic aid significantly influenced FAA during maximum effort cycling. Those athletes with a more pronounced goal seeking persistence and an overall dominance of the BAS over the BIS showed a significantly greater increase in FAA in response to a placebo ergogenic aid. A more pronounced BIS, however, seems to antagonize the increase in FAA associated with the ergogenic placebo response.

Environmental enrichment in porcine farms improves animal welfare and leads to better public acceptance. To better understand the neurological mechanisms of the response to environmental enrichment, monoaminergic neurotransmitters were quantified in several brain areas from pigs after eight weeks of housing in barren or enriched conditions. Furthermore, iTRAQ labelling combined with LC-MS/MS was used to identify differentially abundant proteins in the hippocampus. Blood biochemical parameters related with stress and welfare were measured. Pigs under enriched conditions showed a decrease in plasma cortisol and lactate. The decrease in noradrenaline in the prefrontal cortex and amygdala, a general decrease in the dopaminergic system and an increase of serotonin in the striatum indicate a lower response to stress in enriched conditions. In the proteomic analysis, 2304 proteins were identified, of which 56 were differential between housing groups (46 upregulated and 10 downregulated). Bioinformatics analysis revealed that they were mainly related to ribosome, translation, microtubules and metabolic mitochondrial processes, indicating that pigs under enriched environments have higher abundance of proteins related to protein synthesis and neuronal activity. Together with previous behavioural studies, our results suggest that environmental enrichment provides a less stressful environment and that pigs cope better with stress conditions like the slaughterhouse. SIGNIFICANCE: Animal welfare has become an important aspect for the sustainability of animal production. The modification of the environment by enriching it with rooting materials and wider space allowance is known to have a positive effect on pigs' welfare. Searching for the underlying neurobiological mechanisms, we found that housing in an enriched environment increased the abundance of proteins related to protein synthesis, microtubule assembly, vesicle-mediated transport and energy metabolism in the hippocampus of pigs. Likewise, changes in the neurotransmitter profile in several brain areas were compatible with a better response to stress. This study expands the knowledge about the biological basis of animal welfare-promoting actions.

Impairment of insulin action and metabolic dysregulation have traditionally been associated with schizophrenia, although the molecular basis of such association remains still elusive. The present meta-analysis aims to assess the impact of insulin action manipulations (i.e., hyperinsulinemia, hypoinsulinemia, systemic or brain insulin resistance) on glutamatergic, dopaminergic, γ-aminobutyric acid (GABA)ergic, and serotonergic pathways in the central nervous system. More than one hundred outcomes, including transcript or protein levels, kinetic parameters, and other components of the neurotransmitter pathways, were collected from cultured cells, animals, or humans, and meta-analyzed by applying a random-effects model and adopting Hedges'g to compare means. Two hundred fifteen studies met the inclusion criteria, of which 180 entered the quantitative synthesis. Significant impairments in key regulators of synaptic plasticity processes were detected as the result of insulin handlings. Specifically, protein levels of N-methyl-D-aspartate receptor (NMDAR) subunits including type 2A (NR2A) (Hedges' g = -0.95, 95%C.I. = -1.50, -0.39; p = 0.001; I2 = 47.46%) and 2B (NR2B) (Hedges'g = -0.69, 95%C.I. = -1.35, -0.02; p = 0.043; I2 = 62.09%), and Postsynaptic density protein 95 (PSD-95) (Hedges'g = -0.91, 95%C.I. = -1.51, -0.32; p = 0.003; I2 = 77.81%) were found reduced in insulin-resistant animal models. Moreover, insulin-resistant animals showed significantly impaired dopamine transporter activity, whereas the dopamine D2 receptor mRNA expression (Hedges'g = 3.259; 95%C.I. = 0.497, 6.020; p = 0.021; I2 = 90.61%) increased under insulin deficiency conditions. Insulin action modulated glutamate and GABA release, as well as several enzymes involved in GABA and serotonin synthesis. These results suggest that brain neurotransmitter systems are susceptible to insulin signaling abnormalities, resembling the discrete psychotic disorders' neurobiology and possibly contributing to the development of neurobiological hallmarks of treatment-resistant schizophrenia.