Structural and functional plasticity of the human brain in posttraumatic stress disorder

Bremner, J. Douglas; Elzinga, Bernet M.; Schmahl, Christian; Vermetten, Eric

doi:10.1016/s0079-6123(07)67012-5

Cited by 290 publications

(211 citation statements)

References 130 publications

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“…Thus, our findings are not only significant in the context of psychiatric disorders (e.g., post‐traumatic stress disorder) but extend to a wider spectrum of states, including nosocomial interventions (e.g., patients who show oversensitivity to dental intervention‐induced pain; Klepac et al , 1980). Considering that the maintenance of heightened NE activity in the cerebral cortex characterizes the transition from acute to chronic stress (Arnsten, 2009), our findings might gain importance as a druggable cellular platform (e.g., CNTFRα inhibitors or modulators of Ca 2+ ‐sensor proteins) to combat devastating human neuropsychiatric conditions (Bremner et al , 2008). …”

Section: Discussionmentioning

confidence: 98%

Hypothalamic CNTF volume transmission shapes cortical noradrenergic excitability upon acute stress

et al. 2018

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Stress‐induced cortical alertness is maintained by a heightened excitability of noradrenergic neurons innervating, notably, the prefrontal cortex. However, neither the signaling axis linking hypothalamic activation to delayed and lasting noradrenergic excitability nor the molecular cascade gating noradrenaline synthesis is defined. Here, we show that hypothalamic corticotropin‐releasing hormone‐releasing neurons innervate ependymal cells of the 3rd ventricle to induce ciliary neurotrophic factor (CNTF) release for transport through the brain's aqueductal system. CNTF binding to its cognate receptors on norepinephrinergic neurons in the locus coeruleus then initiates sequential phosphorylation of extracellular signal‐regulated kinase 1 and tyrosine hydroxylase with the Ca2+‐sensor secretagogin ensuring activity dependence in both rodent and human brains. Both CNTF and secretagogin ablation occlude stress‐induced cortical norepinephrine synthesis, ensuing neuronal excitation and behavioral stereotypes. Cumulatively, we identify a multimodal pathway that is rate‐limited by CNTF volume transmission and poised to directly convert hypothalamic activation into long‐lasting cortical excitability following acute stress.

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Section: Discussionmentioning

confidence: 98%

Hypothalamic CNTF volume transmission shapes cortical noradrenergic excitability upon acute stress

et al. 2018

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“…A number of studies have supported the involvement of additional mechanisms in the detrimental effects of stress on hippocampal structure and function (68,77), including activation of glutamate (43,45,49,63), serotonin (27,37,42,47), and GABA (78) receptors. The resulting downstream processes might be reversed by antidepressants including lithium (55,79), tianeptine, and agomelatine (28,63), potentially via cellular cascades including neural cell adhesion molecules (47,79).…”

Section: Discussionmentioning

confidence: 99%

“…A large body of work has demonstrated that chronic stress may result in memory deficits (26)(27)(28)(29)(30)(31) and abnormal LTP (32)(33)(34), and these functional deficits often are accompanied by diminished dendritic arborization (35)(36)(37)(38)(39)(40)(41)(42). Short-term or acute stress, lasting minutes to hours, also has been found to affect memory (43)(44)(45)(46)(47). In parallel, short-term stress has been reported to influence LTP (48)(49)(50)(51)(52) and reduce the density of dendritic spines in area CA1 (44,53) or area CA3 (51,54).…”

mentioning

confidence: 99%

Correlated memory defects and hippocampal dendritic spine loss after acute stress involve corticotropin-releasing hormone signaling

Chen¹,

Rex

Rice

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

238

206

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Stress affects the hippocampus, a brain region crucial for memory. In rodents, acute stress may reduce density of dendritic spines, the location of postsynaptic elements of excitatory synapses, and impair long-term potentiation and memory. Steroid stress hormones and neurotransmitters have been implicated in the underlying mechanisms, but the role of corticotropin-releasing hormone (CRH), a hypothalamic hormone also released during stress within hippocampus, has not been elucidated. In addition, the causal relationship of spine loss and memory defects after acute stress is unclear. We used transgenic mice that expressed YFP in hippocampal neurons and found that a 5-h stress resulted in profound loss of learning and memory. This deficit was associated with selective disruption of long-term potentiation and of dendritic spine integrity in commissural/associational pathways of hippocampal area CA3. The degree of memory deficit in individual mice correlated significantly with the reduced density of area CA3 apical dendritic spines in the same mice. Moreover, administration of the CRH receptor type 1 (CRFR 1 ) blocker NBI 30775 directly into the brain prevented the stress-induced spine loss and restored the stress-impaired cognitive functions. We conclude that acute, hours-long stress impairs learning and memory via mechanisms that disrupt the integrity of hippocampal dendritic spines. In addition, establishing the contribution of hippocampal CRH-CRFR 1 signaling to these processes highlights the complexity of the orchestrated mechanisms by which stress impacts hippocampal structure and function.corticotropin-releasing factor| long-term potentiation | memory | synaptic plasticity | hippocampus T he hippocampal formation is involved in a circuit that is required for several types of memory in both humans and rodents (1-4). At the physiological/cellular level, memory processes generally are believed to involve long-term potentiation (LTP) of synaptic function (5-8). This potentiation, in turn, is associated with an increase in the size (9, 10) and altered composition (11-13) of dendritic spines of hippocampal principal cells that carry excitatory synapses (14, 15).Stress affects both the function and the structure of the hippocampus (16)(17)(18)(19)(20)(21)(22)(23)(24)(25). A large body of work has demonstrated that chronic stress may result in memory deficits (26-31) and abnormal LTP (32-34), and these functional deficits often are accompanied by diminished dendritic arborization (35-42). Short-term or acute stress, lasting minutes to hours, also has been found to affect memory (43-47). In parallel, short-term stress has been reported to influence LTP (48-52) and reduce the density of dendritic spines in area CA1 (44, 53) or area CA3 (51, 54). Whereas hippocampus-mediated memory deficits commonly were associated with-and perhaps result from-loss of synapse-bearing dendrites and dendritic spines, this association has not been universal (37,46,55), so that the structure-function relationship underlying the effects of st...

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“…Aberrant plasticity is believed to underlie the hypersensitivity and abnormal memory retention that accompanies PTSD [93,94], and reversal of this maladaptive plasticity may reduce the exaggerated fear response [95]. Prolonged exposure therapy, which involves repeated recall of an anxiety-inducing situation in a safe environment, provides a degree of desensitization that reduces the fearful response [96,97].…”

Section: Preclinical Studies For Post-traumatic Stress Disordermentioning

confidence: 99%

Enhancing Rehabilitative Therapies with Vagus Nerve Stimulation

Hays

2016

Neurotherapeutics

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Pathological neural activity could be treated by directing specific plasticity to renormalize circuits and restore function. Rehabilitative therapies aim to promote adaptive circuit changes after neurological disease or injury, but insufficient or maladaptive plasticity often prevents a full recovery. The development of adjunctive strategies that broadly support plasticity to facilitate the benefits of rehabilitative interventions has the potential to improve treatment of a wide range of neurological disorders. Recently, stimulation of the vagus nerve in conjunction with rehabilitation has emerged as one such potential targeted plasticity therapy. Vagus nerve stimulation (VNS) drives activation of neuromodulatory nuclei that are associated with plasticity, including the cholinergic basal forebrain and the noradrenergic locus coeruleus. Repeatedly pairing brief bursts of VNS sensory or motor events drives robust, event-specific plasticity in neural circuits. Animal models of chronic tinnitus, ischemic stroke, intracerebral hemorrhage, traumatic brain injury, and post-traumatic stress disorder benefit from delivery of VNS paired with successful trials during rehabilitative training. Moreover, mounting evidence from pilot clinical trials provides an initial indication that VNS-based targeted plasticity therapies may be effective in patients with neurological diseases and injuries. Here, I provide a discussion of the current uses and potential future applications of VNS-based targeted plasticity therapies in animal models and patients, and outline challenges for clinical implementation.

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Structural and functional plasticity of the human brain in posttraumatic stress disorder

Cited by 290 publications

References 130 publications

Hypothalamic CNTF volume transmission shapes cortical noradrenergic excitability upon acute stress

Hypothalamic CNTF volume transmission shapes cortical noradrenergic excitability upon acute stress

Correlated memory defects and hippocampal dendritic spine loss after acute stress involve corticotropin-releasing hormone signaling

Enhancing Rehabilitative Therapies with Vagus Nerve Stimulation

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