Neuromodulators, stress and plasticity: a role for endocannabinoid signalling

Abstract

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-...

Neurobiological Interactions Between Stress and the Endocannabinoid System

“…Retrograde eCB signaling mediates multiple forms of synaptic plasticity, such as long-term depression (LTD) or depolarizationinduced suppression of inhibition/excitation (DSI/E). Recently, the effects of stress on synaptic transmission and plasticity have become a growing area of research (reviewed in (Joels et al, 2009;Popoli et al, 2011;Senst and Bains, 2014;Bains et al, 2015). As discussed, the CB1 receptor is expressed throughout the brain and is present on glutamate and GABA synapses in stress-sensitive circuits, such as the hypothalamus, mPFC, hippocampus, and amygdala.…”

Organismal stress, telomeres and life histories

“…In this case, the longterm effect on the phenotype came about through a direct effect of stressful environments on the chicks, rather than via effects of stressful environments on their mothers. Such effects could come about through routes such as early life 'programming' of the glucocorticoid and endocannabinoid systems in the brain [see Senst and Bains in this issue for details of this system (Senst and Bains, 2014)]. However, in other studies, for example in chickens, early life stress resulted in a dampening of the stress response (Goerlich et al, 2012), which has also been found in some other bird species and in rodents (Marasco et al, 2012).…”

Endocannabinoid-mediated retrograde modulation of synaptic transmission

“…It was proposed that a tonic level of anandamide within the basolateral amygdala provides a steady-state inhibition of HPA axis activity, and that glucocorticoid-induced 2-AG release from paraventricular nucleus neurons mediates rapid negative feedback effects of glucocorticoids on the HPA axis [37]. Conversely, stress-induced HPA axis activity alters the endocannabinoid system, either positively or negatively depending on the brain region, age and conditions of stress, in several brain regions including the hippocampus, amygdala, hypothalamus, nucleus accumbens and prefrontal cortex [6,37,51]. For example, repetitive immobilization stress impaired DSI/DSE by down-regulating CB 1 receptors in the paraventricular nucleus of the hypothalamus [52], whereas chronic stress enhanced DSI partially by down-regulating MGL in the basolateral amygdala [53].…”