Stress Switches Cannabinoid Type-1 (CB<sub>1</sub>) Receptor-Dependent Plasticity from LTD to LTP in the Bed Nucleus of the Stria Terminalis

492

522

Stress affects a constellation of physiological systems in the body and evokes a rapid shift in many neurobehavioral processes. A growing body of work indicates that the endocannabinoid (eCB) system is an integral regulator of the stress response. In the current review, we discuss the evidence to date that demonstrates stress-induced regulation of eCB signaling and the consequential role changes in eCB signaling have with respect to many of the effects of stress. Across a wide array of stress paradigms, studies have generally shown that stress evokes bidirectional changes in the two eCB molecules, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), with stress exposure reducing AEA levels and increasing 2-AG levels. Additionally, in almost every brain region examined, exposure to chronic stress reliably causes a downregulation or loss of cannabinoid type 1 (CB1) receptors. With respect to the functional role of changes in eCB signaling during stress, studies have demonstrated that the decline in AEA appears to contribute to the manifestation of the stress response, including activation of the hypothalamic-pituitary-adrenal (HPA) axis and increases in anxiety behavior, while the increased 2-AG signaling contributes to termination and adaptation of the HPA axis, as well as potentially contributing to changes in pain perception, memory and synaptic plasticity. More so, translational studies have shown that eCB signaling in humans regulates many of the same domains and appears to be a critical component of stress regulation, and impairments in this system may be involved in the vulnerability to stress-related psychiatric conditions, such as depression and posttraumatic stress disorder. Collectively, these data create a compelling argument that eCB signaling is an important regulatory system in the brain that largely functions to buffer against many of the effects of stress and that dynamic changes in this system contribute to different aspects of the stress response.

Section: Functional Role Of Ecb Signaling In the Neurobiological Effementioning

confidence: 55%

Neurobiological Interactions Between Stress and the Endocannabinoid System

Morena

Patel

Bains

et al. 2015

492

522

“…If alterations in BNST structure, function, or connectivity indeed underlie these disorders in humans, then the BNST becomes a novel, untapped treatment target. Supporting this potentially novel role is evidence from rodent studies that anxiety and addiction processes may be altered by drugs that target the BNST, including CRF antagonists (Walker et al, 2009), norepinephrine agonists (Park et al, 2013;Harris and Gewirtz, 2004) and antagonists (Wenzel et al, 2014), and endocannabinoid system targets (Glangetas et al, 2013).…”

Section: The Human Bnstmentioning

confidence: 99%

The Human BNST: Functional Role in Anxiety and Addiction

Avery

Clauss

Blackford

2015

268

206

The consequences of chronic stress on brain structure and function are far reaching. Whereas stress can produce short-term adaptive changes in the brain, chronic stress leads to long-term maladaptive changes that increase vulnerability to psychiatric disorders, such as anxiety and addiction. These two disorders are the most prevalent psychiatric disorders in the United States, and are typically chronic, disabling, and highly comorbid. Emerging evidence implicates a tiny brain region-the bed nucleus of the stria terminalis (BNST)-in the body's stress response and in anxiety and addiction. Rodent studies provide compelling evidence that the BNST plays a central role in sustained threat monitoring, a form of adaptive anxiety, and in the withdrawal and relapse stages of addiction; however, little is known about the role of BNST in humans. Here, we review current evidence for BNST function in humans, including evidence for a role in the production of both adaptive and maladaptive anxiety. We also review preliminary evidence of the role of BNST in addiction in humans. Together, these studies provide a foundation of knowledge about the role of BNST in adaptive anxiety and stress-related disorders. Although the field is in its infancy, future investigations of human BNST function have tremendous potential to illuminate mechanisms underlying stressrelated disorders and identify novel neural targets for treatment.

“…Stress is known to cause a long-lasting increase in anxiety-like behavior, and as the BNST is a crucial structure in modulating both the stress response and anxiety behavior, it is reasonable to predict that stress would cause a long-lasting change in BNST synaptic plasticity. In fact, multiple studies have shown that stress can affect synaptic plasticity in the BNST (Conrad et al, 2011;Dabrowska et al, 2013b;Francesconi et al, 2009;Glangetas et al, 2013;McElligott and Winder, 2007), however the results of these studies are seemingly inconsistent. In this section, we will re-examine these studies in light of how stress interacts with neuromodulators as discussed above and new research on the distinct roles of different BNST sub-nuclei in modulating anxiety-like behavior.…”

Section: Stress Modulation Of Synaptic Plasticitymentioning

confidence: 99%

“…Acute stress can cause a 10 Hz stimulation of the medial prefrontal cortex (mPFC) input into the BNST to switch from resulting in a long-term depression (LTD) to a long-term potentiation (LTP). The functional consequence of this switch from LTD to LTP is unknown; perhaps it acts to boost the signal of salient events after acute stress (Glangetas et al, 2013). The BNST serves as a relay between the mPFC and VTA DA neurons.…”

Section: Stress Modulation Of Synaptic Plasticitymentioning

confidence: 99%

Stress Modulation of Opposing Circuits in the Bed Nucleus of the Stria Terminalis

Daniel

Rainnie

2015

174

191

The anterior bed nucleus of the stria terminalis (BNST) has been recognized as a critical structure in regulating trait anxiety, contextual fear memory, and appetitive behavior, and is known to be sensitive to stress manipulations. As one of the most complex structures in the central nervous system, the intrinsic circuitry of the BNST is largely unknown; however, recent technological developments have allowed researchers to begin to untangle the internal connections of the nucleus. This research has revealed the possibility of two opposing circuits, one anxiolytic and one anxiogenic, within the BNST, the relative strength of which determines the behavioral outcome. The balance of these pathways is critical in maintaining a normal physiological and behavioral state; however, stress and drugs of abuse can differentially affect the opposing circuitry within the nucleus to shift the balance to a pathological state. In this review, we will examine how stress interacts with the neuromodulators, corticotropin-releasing factor, norepinephrine, dopamine, and serotonin to affect the circuitry of the BNST as well as how synaptic plasticity in the BNST is modulated by stress, resulting in long-lasting changes in the circuit and behavioral state.