Many species use social networks to buffer the effects of stress. The mere absence of a social network, however, may also be stressful. We examined neuroendocrine, PVN CRH neurons and report that social isolation alters the intrinsic properties of these cells in sexually dimorphic fashion. Specifically, isolating preadolescent female mice from littermates for <24 hr increased first spike latency (FSL) and decreased excitability of CRH neurons. These changes were not evident in age-matched males. By contrast, subjecting either males (isolated or grouped) or group housed females to acute physical stress (swim), increased FSL. The increase in FSL following either social isolation or acute physical stress was blocked by the glucocorticoid synthesis inhibitor, metyrapone and mimicked by exogenous corticosterone. The increase in FSL results in a decrease in the excitability of CRH neurons. Our observations demonstrate that social isolation, but not acute physical stress has sex-specific effects on PVN CRH neurons.DOI: http://dx.doi.org/10.7554/eLife.18726.001

Alterations in synaptic endocannabinoid signaling are a widespread neurobiological consequence of many in vivo experiences, including stress. Here, we report that stressor salience is critical for bidirectionally modifying presynaptic CB-1 receptor (CB1R) function at hypothalamic GABA synapses controlling the neuroendocrine stress axis in male rats. While repetitive, predictable stressor exposure impairs presynaptic CB1R function, these changes are rapidly reversed upon exposure to a high salience experience such as novel stress or by manipulations that enhance neural activity levels in vivo or in vitro. Together these data demonstrate that experience salience, through alterations in afferent synaptic activity, induces rapid changes in endocannabinoid signaling.

Any unanticipated threat to survival triggers an immediate sequence of events in the brain that culminate in a coordinated neural, endocrine and behavioural response. There is increasing evidence that stress itself modifies neural circuits. In other words, neural stress circuits learn from stress. This self-teaching is surprising as one might expect these essential circuits to be hard-wired. Our recent findings, however, indicate that repeated homotypic stress in rats causes functional changes in neural circuitry in the hypothalamus. In particular, we focus on signalling via endocannabinoids and describe plasticity in this system that impacts fast retrograde signalling at synapses on to the stress command neurons in the brain. Interestingly, this plasticity appears to be limited to early adolescence, hinting at unique modes of control of neural circuits by stress during different developmental stages. KEY WORDS: Hypothalamus, Neuromodulation, Neurobiology IntroductionIn all organisms, maintaining a stable internal environment and responding to external threats is vital for survival. This requires the ability to sense, transduce and respond effectively to real and perceived stress. In mammals, multiple brain nuclei are activated in response to both physiological and psychological challenges. When faced with a challenge to internal homeostasis or an unanticipated, direct threat to survival, this 'stress circuitry' rapidly sets in motion a cascade of neural, neuroendocrine and behavioural responses. Mounting an appropriate physiological response to such challenges requires that the brain interprets, learns from and then remembers the appropriate stimuli. This series of tasks is accomplished by groups of interconnected neural networks that incorporate information from sensory systems, process this information in higher brain centres then engage downstream effectors to coordinate generalized behavioural and physiological adaptation to change. In the short-term, these adaptations are beneficial as they allow the organism to respond to the threat. They also promote learning, which results in more refined responses to subsequent challenges. When launched inappropriately, however -for example, in the absence of stress -they can have deleterious effects on mental and physical health (McEwen and Gianaros, 2011;Stetler and Miller, 2011).At the organismal level, stress is a complicated response to study as there are a myriad of genetic, environmental and social contributions that influence how the body is designed to respond to challenges (Russo et al., 2012). In addition, the network of mediators that influence neural and neuroendocrine responses function in a non-linear fashion (McEwen, 2006). In an effort to better understand how the neuroendocrine response to stress is initiated and modified, we have focused exclusively on synapses that provide direct input to parvocellular neurosecretory cells (PNCs) in the paraventricular nucleus of the hypothalamus (PVN). These cells are the apex of the hypothalamic-pituitary-...

Many species use social networks to buffer the effects of stress. The mere absence of a social network, however, may also be stressful. We examined neuroendocrine, PVN CRH neurons and report that social isolation alters the intrinsic properties of these cells in sexually dimorphic fashion. Specifically, isolating preadolescent female mice from littermates for <24 hr increased first spike latency (FSL) and decreased excitability of CRH neurons. These changes were not evident in age-matched males. By contrast, subjecting either males (isolated or grouped) or group housed females to acute physical stress (swim), increased FSL. The increase in FSL following either social isolation or acute physical stress was blocked by the glucocorticoid synthesis inhibitor, metyrapone and mimicked by exogenous corticosterone. The increase in FSL results in a decrease in the excitability of CRH neurons. Our observations demonstrate that social isolation, but not acute physical stress has sex-specific effects on PVN CRH neurons.