A brain circuit is identified through which serotonin induces an anxiety-like state; this circuit also mediates the anxiety-like behaviour induced by acute administration of the selective serotonin reuptake inhibitor fluoxetine and may underlie the early adverse events that some patients with anxiety disorders have to these types of drugs. The circuits through which serotonin regulates mood are not well understood. Here Thomas Kash and colleagues describe a mechanism by which serotonin induces an anxiety-like state in mice. They show that serotonergic projections from the dorsal raphe nuclei to the bed nucleus of the stria terminalis (BNST), a forebrain structure involved in controlling autonomic, neuroendocrine and behavioural responses, activate corticotropin-releasing factor (CRF) neurons that inhibit anxiolytic outputs from the BNST to the ventral tegmental area and lateral hypothalamus. They further show that this circuit mediates anxiety-like behaviour induced by acute administration of the serotonin reuptake inhibitor (SSRI) fluoxetine. The authors suggest that a similar mechanism may underlie the early adverse reactions to SSRI treatment that have been shown to occur in some patients with anxiety disorders. Serotonin (also known as 5-hydroxytryptamine (5-HT)) is a neurotransmitter that has an essential role in the regulation of emotion. However, the precise circuits have not yet been defined through which aversive states are orchestrated by 5-HT. Here we show that 5-HT from the dorsal raphe nucleus (5-HTDRN) enhances fear and anxiety and activates a subpopulation of corticotropin-releasing factor (CRF) neurons in the bed nucleus of the stria terminalis (CRFBNST) in mice. Specifically, 5-HTDRN projections to the BNST, via actions at 5-HT2C receptors (5-HT2CRs), engage a CRFBNST inhibitory microcircuit that silences anxiolytic BNST outputs to the ventral tegmental area and lateral hypothalamus. Furthermore, we demonstrate that this CRFBNST inhibitory circuit underlies aversive behaviour following acute exposure to selective serotonin reuptake inhibitors (SSRIs). This early aversive effect is mediated via the corticotrophin-releasing factor type 1 receptor (CRF1R, also known as CRHR1), given that CRF1R antagonism is sufficient to prevent acute SSRI-induced enhancements in aversive learning. These results reveal an essential 5-HTDRN→CRFBNST circuit governing fear and anxiety, and provide a potential mechanistic explanation for the clinical observation of early adverse events to SSRI treatment in some patients with anxiety disorders1,2.

The human gut is a composite anaerobic environment with a large, diverse and dynamic enteric microbiota, represented by more than 100 trillion microorganisms, including at least 1000 distinct species. The discovery that a different microbial composition can influence behavior and cognition, and in turn the nervous system can indirectly influence enteric microbiota composition, has significantly contributed to establish the well-accepted concept of gut-brain axis. This hypothesis is supported by several evidence showing mutual mechanisms, which involve the vague nerve, the immune system, the hypothalamic-pituitaryadrenal (HPA) axis modulation and the bacteria-derived metabolites. Many studies have focused on delineating a role for this axis in health and disease, ranging from stress-related disorders such as depression, anxiety and irritable bowel syndrome (IBS) to neurodevelopmental disorders, such as autism, and to neurodegenerative diseases, such as Parkinson Disease, Alzheimer’s Disease etc. Based on this background, and considering the relevance of alteration of the symbiotic state between host and microbiota, this review focuses on the role and the involvement of bioactive lipids, such as the N-acylethanolamine (NAE) family whose main members are N-arachidonoylethanolamine (AEA), palmitoylethanolamide (PEA) and oleoilethanolamide (OEA), and short chain fatty acids (SCFAs), such as butyrate, belonging to a large group of bioactive lipids able to modulate peripheral and central pathologic processes. Their effective role has been studied in inflammation, acute and chronic pain, obesity and central nervous system diseases. A possible correlation has been shown between these lipids and gut microbiota through different mechanisms. Indeed, systemic administration of specific bacteria can reduce abdominal pain through the involvement of cannabinoid receptor 1 in the rat; on the other hand, PEA reduces inflammation markers in a murine model of inflammatory bowel disease (IBD), and butyrate, producted by gut microbiota, is effective in reducing inflammation and pain in irritable bowel syndrome and IBD animal models. In this review, we underline the relationship among inflammation, pain, microbiota and the different lipids, focusing on a possible involvement of NAEs and SCFAs in the gut-brain axis and their role in the central nervous system diseases.

Alterations of microbiota-gut-brain axis have been invoked in the pathogenesis of autism spectrum disorders (ASD). Mouse models could represent an excellent tool to understand how gut dysbiosis and related alterations may contribute to autistic phenotype. In this study we paralleled gut microbiota (GM) profiles, behavioral characteristics, intestinal integrity and immunological features of colon tissues in BTBR T + tf/J (BTBR) inbred mice, a well established animal model of ASD. Sex differences, up to date poorly investigated in animal models, were specifically addressed. Results showed that BTBR mice of both sexes presented a marked intestinal dysbiosis, alterations of behavior, gut permeability and immunological state with respect to prosocial C57BL/6j (C57) strain. Noticeably, sex-related differences were clearly detected. We identified Bacteroides, Parabacteroides, Sutterella, Dehalobacterium and Oscillospira genera as key drivers of sex-specific gut microbiota profiles associated with selected pathological traits. Taken together, our findings indicate that alteration of GM in BTBR mice shows relevant sex-associated differences and supports the use of BTBR mouse model to dissect autism associated microbiota-gut-brain axis alteration.

The nucleus of the solitary tract (NTS) is a key gateway for meal-related signals entering the brain from the periphery. However, the chemical mediators crucial to this process have not been fully elucidated. We reveal that a subset of NTS neurons containing cholecystokinin (CCK^NTS) is responsive to nutritional state and that their activation reduces appetite and body weight in mice. Cell-specific anterograde tracing revealed that CCK^NTS neurons provide a distinctive innervation of the paraventricular nucleus of the hypothalamus (PVH), with fibers and varicosities in close apposition to a subset of melanocortin-4 receptor (MC4R^PVH) cells, which are also responsive to CCK. Optogenetic activation of CCK^NTS axon terminals within the PVH reveal the satiating function of CCK^NTS neurons to be mediated by a CCK^NTS→PVH pathway that also encodes positive valence. These data identify the functional significance of CCK^NTS neurons and reveal a sufficient and discrete NTS to hypothalamus circuit controlling appetite.

Background and purpose: Alzheimer's disease (AD) is a common neurodegenerative disease characterized by a neuroinflammatory state, and to date, there is no cure and its treatment represents a large unmet clinical need. The involvement of Th17 cells in the pathogenesis of AD‐related neuroinflammation has been reported in several studies. However, the role of the cytokine, IL‐17 has not been well addressed. Herein, we investigate the effects of IL‐17 neutralizing antibody (IL‐17Ab) injected by i.c.v. or intranasal (IN) routes on amyloid‐β (Aβ)‐induced neuroinflammation and memory impairment in mice.Experimental approach: Aβ_1–42 was injected into cerebral ventricles of adult CD1 mice. These mice received IL‐17Ab via i.c.v. either at 1 h prior to Aβ_1–42 injection or IN 5 and 12 days after Aβ_1–42 injection. After 7 and 14 days of Aβ_1–42 administration, we evaluated olfactory, spatial and working memory and performed biochemical analyses on whole brain and specific brain areas.Key results: Pretreatment with IL‐17Ab, given, i.c.v., markedly reduced Aβ_1–42‐induced neurodegeneration, improved memory function, and prevented the increase of pro‐inflammatory mediators in a dose‐dependent manner at 7 and 14 days. Similarly, the double IN administration of IL‐17Ab after Aβ_1–42 injection reduced neurodegeneration, memory decline, and the levels of proinflammatory mediators and cytokines.Conclusion and implications: These findings suggest that the IL‐17Ab reduced neuroinflammation and behavioural symptoms induced by Aβ. The efficacy of IL‐17Ab IN administration in reducing Aβ_1–42 neurodegeneration points to a possible future therapeutic approach in patients with AD.Linked Articles: This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc