Hedonic eating, obesity, and addiction result from increased neuropeptide Y in the nucleus accumbens during human brain evolution.

The nucleus accumbens (NAc) is central to motivation and action, exhibiting one of the highest densities of neuropeptide Y (NPY) in the brain. Within the NAc, NPY plays a role in reward and is involved in emotional behavior and in increasing alcohol and drug addiction and fat intake. Here, we examined NPY innervation and neurons of the NAc in humans and other anthropoid primates in order to determine whether there are differences among these various species that would correspond to behavioral or life history variables. We quantified NPY-immunoreactive axons and neurons in the NAc of 13 primate species, including humans, great apes, and monkeys. Our data show that the human brain is unique among primates in having denser NPY innervation within the NAc, as measured by axon length density to neuron density, even after accounting for brain size. Combined with our previous finding of increased dopaminergic innervation in the same region, our results suggest that the neurochemical profile of the human NAc appears to have rendered our species uniquely susceptible to neurophysiological conditions such as addiction. The increase in NPY specific to the NAc may represent an adaptation that favors fat intake and contributes to an increased vulnerability to eating disorders, obesity, as well as alcohol and drug dependence. Along with our findings for dopamine, these deeply rooted structural attributes of the human brain are likely to have emerged early in the human clade, laying the groundwork for later brain expansion and the development of cognitive and behavioral specializations.

T-cell derived acetylcholine aids host defenses during enteric bacterial infection with Citrobacter rodentium.

The regulation of mucosal immune function is critical to host protection from enteric pathogens but is incompletely understood. The nervous system and the neurotransmitter acetylcholine play an integral part in host defense against enteric bacterial pathogens. Here we report that acetylcholine producing-T-cells, as a non-neuronal source of ACh, were recruited to the colon during infection with the mouse pathogen Citrobacter rodentium. These ChAT+ T-cells did not exclusively belong to one Th subset and were able to produce IFNγ, IL-17A and IL-22. To interrogate the possible protective effect of acetylcholine released from these cells during enteric infection, T-cells were rendered deficient in their ability to produce acetylcholine through a conditional gene knockout approach. Significantly increased C. rodentium burden was observed in the colon from conditional KO (cKO) compared to WT mice at 10 days post-infection. This increased bacterial burden in cKO mice was associated with increased expression of the cytokines IL-1ß, IL-6, and TNFα, but without significant changes in T-cell and ILC associated IL-17A, IL-22, and IFNγ, or epithelial expression of antimicrobial peptides, compared to WT mice. Despite the increased expression of pro-inflammatory cytokines during C. rodentium infection, inducible nitric oxide synthase (Nos2) expression was significantly reduced in intestinal epithelial cells of ChAT T-cell cKO mice 10 days post-infection. Additionally, a cholinergic agonist enhanced IFNγ-induced Nos2 expression in intestinal epithelial cell in vitro. These findings demonstrated that acetylcholine, produced by specialized T-cells that are recruited during C. rodentium infection, are a key mediator in host-microbe interactions and mucosal defenses.

The Paracingulate Sulcus Is a Unique Feature of the Medial Frontal Cortex Shared by Great Apes and Humans.

Primate brains display a wide range of variation in size and cerebral gyrification, leading to the appearance of novel sulci in particular groups of species. We investigated sulcal organization in the medial frontal cortex of great apes, with a particular focus on the paracingulate sulcus (PCGS). Until recently, the presence of the PCGS was thought to be a structural feature unique to the human brain. However, upon closer examination, the PCGS has been observed as a variable feature that also may appear in chimpanzee brains. To understand the evolutionary origins of the sulcal anatomy in the medial frontal cortex of apes, we examined high-resolution MRI scans for the presence or absence of the PCGS and, when present, measured its length in a sample of ape brains (chimpanzees, bonobos, gorillas, orangutans, gibbons, and siamangs). We found that the PCGS is variable in its appearance among these species, being present in 23 to 50% of great ape individuals depending on the species, but not present in gibbons or siamangs. We did not find population level hemispheric lateralization patterns or sex differences in PCGS presence across species, and we did not detect a relationship between cerebral volume and PCGS occurrence or length. Our data suggest that the PCGS is a common sulcal variant present in great apes and humans due to a shared evolutionary ancestry.

Modulation of the microbiota-gut-brain axis by probiotics in a murine model of inflammatory bowel disease.

UNLABELLED: Anxiety, depression, and altered memory are associated with intestinal diseases, including inflammatory bowel disease (IBD). Understanding the link between these behavioral changes and IBD is important clinically since concomitant mood disorders often increase a patient's risk of requiring surgery and developing secondary functional gastrointestinal diseases. Anxiety-like behavior (light/dark box test) and recognition memory (novel object recognition task) were determined at the peak and during resolution of inflammation in the dextran sodium sulfate (DSS) mouse model of acute colitis. DSS (5 days) was administered via drinking water followed by 3 or 9 days of normal drinking water to assess behavior during active or resolving inflammation, respectively. Disease (weight, colon length, and histology) was assessed and the composition of the gut microbiota was characterized by using qPCR on fecal pellet DNA. In a subset of mice, pretreatment with probiotics was started 1 wk prior to commencing DSS. During active inflammation (8 days), mice demonstrated impaired recognition memory and exhibited anxiety-like behavior vs. CONTROLS: These behavioral defects were normalized by 14 days post-DSS. Shifts in the composition of the gut microbiota were evident during active inflammation, notably as decreases in lactobacilli and segmented filamentous bacteria, which were also reversed once the disease had resolved. Administration of probiotics could prevent the behavioral defects seen in acute DSS. Taken together, our findings indicate that changes in mood and behavior are present during acute inflammation in murine IBD and associated with dysbiosis and that these outcomes can be prevented by the administration of probiotics.

A C. elegans genome-wide RNAi screen for altered levamisole sensitivity identifies genes required for muscle function.

At the neuromuscular junction (NMJ), postsynaptic ionotropic acetylcholine receptors (AChRs) transduce a chemical signal released from a cholinergic motor neuron into an electrical signal to induce muscle contraction. To identify regulators of postsynaptic function, we conducted a genome-wide RNAi screen for genes required for proper response to levamisole, a pharmacological agonist of ionotropic L-AChRs at the Caenorhabditis elegans NMJ. A total of 117 gene knockdowns were found to cause levamisole hypersensitivity, while 18 resulted in levamisole resistance. Our screen identified conserved genes important for muscle function including some that are mutated in congenital myasthenic syndrome, congenital muscular dystrophy, congenital myopathy, myotonic dystrophy, and mitochondrial myopathy. Of the genes found in the screen, we further investigated those predicted to play a role in endocytosis of cell surface receptors. Loss of the Epsin homolog epn-1 caused levamisole hypersensitivity and had opposing effects on the levels of postsynaptic L-AChRs and GABAA receptors, resulting in increased and decreased abundance, respectively. We also examined other genes that resulted in a levamisole-hypersensitive phenotype when knocked down including gas-1, which functions in Complex I of the mitochondrial electron transport chain. Consistent with altered ATP synthesis impacting levamisole response, treatment of wild-type animals with levamisole resulted in L-AChR-dependent depletion of ATP levels. These results suggest that the paralytic effects of levamisole ultimately lead to metabolic exhaustion.

The nucleus accumbens and ventral pallidum exhibit greater dopaminergic innervation in humans compared to other primates.

Recent evidence suggests that increased dopaminergic signaling within the dorsal striatum played a central role in the evolution of the human brain. This increase has been linked to human prosociality and language in what has been described as a dopamine-dominated striatum personality style. Increased striatal dopamine is associated with an increase in ventral striatal activity and promotes externally driven behaviors, including cooperation and social conformity. In contrast, decreased striatal dopamine is associated with increased dorsal striatal activity and favors internally driven and goal-oriented behaviors. Previous comparative studies have focused on the dorsal striatum, measuring dopaminergic innervation in the dorsal and medial caudate nucleus and putamen. Here, we add to this knowledge by examining regions of the ventral striatum. We quantified the density of tyrosine hydroxylase-immunoreactive axons, as a measure of dopaminergic innervation, in the nucleus accumbens and ventral pallidum of humans, great apes, platyrrhine and cercopithecid monkeys. Our data show that humans have a significantly greater dopaminergic innervation in both structures, supporting the hypothesis that selection for a prosocial neurochemistry in the human basal ganglia may have contributed to the evolution of our uniquely social behavior profile.

What single neurons can tell us.

IQ scores are correlated with the morphology and activity of certain neurons in the human temporal cortex.

Developmental exposure to polychlorinated biphenyls (PCBs) in the maternal diet causes host-microbe defects in weanling offspring mice.

The gut microbiota is important for maintaining homeostasis of the host. Gut microbes represent the initial site for toxicant processing following dietary exposures to environmental contaminants. The diet is the primary route of exposure to polychlorinated biphenyls (PCBs), which are absorbed via the gut, and subsequently interfere with neurodevelopment and behavior. Developmental exposures to PCBs have been linked to increased risk of neurodevelopmental disorders (NDD), including autism spectrum disorder (ASD), which are also associated with a high prevalence of gastrointestinal (GI) distress and intestinal dysbiosis. We hypothesized that developmental PCB exposure impacts colonization of the gut microbiota, resulting in GI pathophysiology, in a genetically susceptible host. Mouse dams expressing two heritable human mutations (double mutants [DM]) that result in abnormal Ca2+ dynamics and produce behavioral deficits (gain of function mutation in the ryanodine receptor 1 [T4826I-RYR1] and a human CGG repeat expansion [170-200 CGG repeats] in the fragile X mental retardation gene 1 [FMR1 premutation]). DM and congenic wild type (WT) controls were exposed to PCBs (0-6 mg/kg/d) in the diet starting 2 weeks before gestation and continuing through postnatal day 21 (P21). Intestinal physiology (Ussing chambers), inflammation (qPCR) and gut microbiome (16S sequencing) studies were performed in offspring mice (P28-P30). Developmental exposure to PCBs in the maternal diet caused significant mucosal barrier defects in ileum and colon (increased secretory state and tight junction permeability) of juvenile DM mice. Furthermore, PCB exposure increased the intestinal inflammatory profile (Il6, Il1ß, and Il22), and resulted in dysbiosis of the gut microbiota, including altered ß-diversity, in juvenile DM mice developmentally exposed to 1 mg/kg/d PCBs when compared to WT controls. Collectively, these findings demonstrate a novel interaction between PCB exposure and the gut microbiota in a genetically susceptible host that provide novel insight into environmental risk factors for neurodevelopmental disorders.

Neurogenic potential of engineered mesenchymal stem cells overexpressing VEGF.

Numerous signaling molecules are altered following nerve injury, serving as a blueprint for drug delivery approaches that promote nerve repair. However, challenges with achieving the appropriate temporal duration of recombinant protein delivery have limited the therapeutic success of this approach. Genetic engineering of mesenchymal stem cells (MSCs) to enhance the secretion of proangiogenic molecules such as vascular endothelial growth factor (VEGF) may provide an alternative. We hypothesized that the administration of VEGF-expressing human MSCs would stimulate neurite outgrowth and proliferation of cell-types involved in neural repair. When cultured with dorsal root ganglion (DRG) explants in vitro, control and VEGF-expressing MSCs (VEGF-MSCs) increased neurite extension and proliferation of Schwann cells (SCs) and endothelial cells, while VEGF-MSCs stimulated significantly greater proliferation of endothelial cells. When embedded within a 3D fibrin matrix, VEGF-MSCs maintained overexpression and expressed detectable levels over 21 days. After transplantation into a murine sciatic nerve injury model, VEGF-MSCs maintained high VEGF levels for 2 weeks. This study provides new insight into the role of VEGF on peripheral nerve injury and the viability of transplanted genetically engineered MSCs. The study aims to provide a framework for future studies with the ultimate goal of developing an improved therapy for nerve repair.