Neuroendocrine Regulation of Anxiety: Beyond the Hypothalamic-Pituitary-Adrenal Axis.

The central nervous system regulates and responds to endocrine signals, and this reciprocal relationship determines emotional processing and behavioural anxiety. Although the hypothalamic-pituitary-adrenal (HPA) axis remains the best-characterised system for this relationship, other steroid and peptide hormones are increasingly recognised for their effects on anxiety-like behaviour and reward. The present review examines recent developments related to the role of a number of different hormones in anxiety, including pregnane neurosteroids, gut peptides, neuropeptides and hormonal signals derived from fatty acids. Findings from both basic and clinical studies suggest that these alternative systems may complement or occlude stress-induced changes in anxiety and anxiety-like behaviour. By broadening the scope of mechanisms for depression and anxiety, it may be possible to develop novel strategies to attenuate stress-related psychiatric conditions. The targets for these potential therapies, as discussed in this review, encompass multiple circuits and systems, including those outside of the HPA axis.

Models and mechanisms for hippocampal dysfunction in obesity and diabetes.

Clinical studies suggest that obesity and Type 2 (insulin-resistant) diabetes impair the structural integrity of medial temporal lobe regions involved in memory and confer greater vulnerability to neurological insults. While eliminating obesity and its endocrine comorbidities would be the most straightforward way to minimize cognitive risk, structural barriers to physical activity and the widespread availability of calorically dense, highly palatable foods will likely necessitate additional strategies to maintain brain health over the lifespan. Research in rodents has identified numerous correlates of hippocampal functional impairment in obesity and diabetes, with several studies demonstrating causality in subsequent mechanistic studies. This review highlights recent work on pathways and cell-cell interactions underlying the synaptic consequences of obesity, diabetes, or in models with both pathological conditions. Although the mechanisms vary across different animal models, immune activation has emerged as a shared feature of obesity and diabetes, with synergistic exacerbation of neuroinflammation in model systems with both conditions. This review discusses these findings with reference to the benefits of incorporating existing models from the fields of obesity and metabolic disease. Many transgenic lines with basal metabolic alterations or differential susceptibility to diet-induced obesity have yet to be characterized with respect to their cognitive and synaptic phenotype. Adopting these models, and building on the extensive knowledge base used to generate them, is a promising avenue for understanding interactions between peripheral disease states and neurodegenerative disorders.

Galanin mediates features of neural and behavioral stress resilience afforded by exercise.

Exercise promotes resilience to stress and increases galanin in the locus coeruleus (LC), but the question of whether changes in galanin signaling mediate the stress-buffering effects of exercise has never been addressed. To test the contributions of galanin to stress resilience, male Sprague Dawley rats received intracerebroventricular (ICV) cannulation for drug delivery and frontocortical cannulation for microdialysis, and were housed with or without a running wheel for 21d. Rats were acutely injected with vehicle or the galanin receptor antagonist M40 and exposed to a single session of either footshock or no stress. Other groups received galanin, the galanin receptor antagonist M40, or vehicle chronically for 21d prior to the stress session. Microdialysis sampling occurred during stress exposure and anxiety-related behavior was measured on the following day in the elevated plus maze. Dendritic spines were visualized by Golgi impregnation in medial prefrontal cortex (mPFC) pyramidal neurons and quantified. Exercise increased galanin levels in the LC. Under non-stressed conditions, anxiety-related behavior and dopamine levels were comparable between exercised and sedentary rats. In contrast, exposure to stress reduced open arm exploration in sedentary rats but not in exercise rats or those treated chronically with ICV galanin, indicating improved resilience. Both exercise and chronic, ICV galanin prevented the increased dopamine overflow and loss of dendritic spines observed after stress in sedentary rats. Chronic, but not acute M40 administration blocked the resilience-promoting effects of exercise. The results indicate that increased galanin levels promote features of resilience at both behavioral and neural levels.

Pharmacomimetics of exercise: novel approaches for hippocampally-targeted neuroprotective agents.

Coordinated and constructive physical activity is correlated with the maintenance of cognitive function in humans. Voluntary running also enhances neuroplasticity in adult and aging rodents, but the molecular pathways underlying these effects are still being elucidated. Considering the multifactorial nature of the biochemical links between physical activity and neurophysiology it is likely that there are many pharmacological mechanisms by which the beneficial actions of exercise can be effectively reproduced using chemical agents. Most studies to date have focused on brain-derived neurotrophic factor (BDNF) as a signaling target for the enhancement of neuronal function by exercise. The goal of the current review is to move beyond BDNF by exploring the diversity of molecular pathways regulated by physical activity in a variety of situations. We will discuss the availability and mechanism of action for several diverse physical activity pharmacomimetics. As physical activity enhances both neuroplasticity and cognition, understanding the molecular targets for these effects may lead to the development of protent new therapeutic interventions for age-related neurodegenerative conditions such as Alzheimer's disease.