The Effects of Stress Exposure on Prefrontal Cortex: Translating Basic Research into Successful Treatments for Post-Traumatic Stress Disorder.

The locus coeruleus norepinephrine (LC-NE) system plays a broad role in learning and memory. Here we begin with an overview of the LC-NE system. We then consider how both direct and indirect manipulations of the LC-NE system affect cued and contextual aversive learning and memory. We propose that NE dynamically modulates Pavlovian conditioning and extinction, either promoting or impairing learning aversive processes under different levels of behavioral arousal. We suggest that under high levels of stress (e.g., during/soon after fear conditioning) the locus coeruleus (LC) promotes cued fear learning by enhancing amygdala function while simultaneously blunting prefrontal function. Under low levels of arousal, the LC promotes PFC function to promote downstream inhibition of the amygdala and foster the extinction of cued fear. Thus, LC-NE action on the medial prefrontal cortex (mPFC) might be described by an inverted-U function such that it can either enhance or hinder learning depending on arousal states. In addition, LC-NE seems to be particularly important for the acquisition, consolidation and extinction of contextual fear memories. This may be due to dense adrenoceptor expression in the hippocampus (HPC) which encodes contextual information, and the ability of NE to regulate long-term potentiation (LTP). Moreover, recent work reveals that the diversity of LC-NE functions in aversive learning and memory are mediated by functionally heterogeneous populations of LC neurons that are defined by their projection targets. Hence, LC-NE function in learning and memory is determined by projection-specific neuromodulation that accompanies various states of behavioral arousal.

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Noradrenergic Modulation of Fear Conditioning and Extinction.

Stress-induced impairments in extinction learning are believed to sustain posttraumatic stress disorder (PTSD). Noradrenergic signaling may contribute to extinction impairments by modulating medial prefrontal cortex (mPFC) circuits involved in fear regulation. Here we demonstrate that aversive fear conditioning rapidly and persistently alters spontaneous single-unit activity in the prelimbic and infralimbic subdivisions of the mPFC in behaving rats. These conditioning-induced changes in mPFC firing were mitigated by systemic administration of propranolol (10 mg/kg, i.p.), a β-noradrenergic receptor antagonist. Moreover, propranolol administration dampened the stress-induced impairment in extinction observed when extinction training is delivered shortly after fear conditioning. These findings suggest that β-adrenoceptors mediate stress-induced changes in mPFC spike firing that contribute to extinction impairments. Propranolol may be a helpful adjunct to behavioral therapy for PTSD, particularly in patients who have recently experienced trauma.

https://www.pnas.org/content/pnas/112/28/E3729.full.pdf

Noradrenergic blockade stabilizes prefrontal activity and enables fear extinction under stress

This review aims to synthesise a large pre-clinical and clinical literature related to a hypothesised role of the locus coeruleus norepinephrine system in responses to acute and chronic threat, as well as the emergence of pathological anxiety. The locus coeruleus has widespread norepinephrine projections throughout the central nervous system, which act to globally modulate arousal states and adaptive behavior, crucially positioned to play a significant role in modulating both ascending visceral and descending cortical neurocognitive information. In response to threat or a stressor, the locus coeruleus-norepinephrine system globally modulates arousal, alerting and orienting functions and can have a powerful effect on the regulation of multiple memory systems. Chronic stress leads to amplification of locus coeruleus reactivity to subsequent stressors, which is coupled with the emergence of pathological anxiety-like behaviors in rodents. While direct in vivo evidence for locus coeruleus dysfunction in humans with pathological anxiety remains limited, recent advances in high-resolution 7-T magnetic resonance imaging and computational modeling approaches are starting to provide new insights into locus coeruleus characteristics.

https://journals.sagepub.com/doi/pdf/10.1177/2398212820930321

The role of the locus coeruleus in the generation of pathological anxiety.

LGBTQ individuals may be at risk for suicidal behavior due to perceived stigma and psychopathology. However, protective factors, such as community connectedness, may reduce risk. We examined depres...

Stigma and suicide risk among the LGBTQ population: Are anxiety and depression to blame and can connectedness to the LGBTQ community help?

Patients with post-traumatic stress disorder (PTSD) are frequently symptomatic despite being on medications currently approved by the US Food and Drug Administration for PTSD. There is evidence to ...

https://journals.sagepub.com/doi/pdf/10.1177/2045125313500982

High-dose prazosin for the treatment of post-traumatic stress disorder

Prenatal alcohol exposure causes persistent neuropsychiatric deficits included under the term fetal alcohol spectrum disorders (FASD). Cellular identity emerges from a cascade of intrinsic and extrinsic (involving cell-cell interactions and signaling) processes that are partially initiated and maintained through changes in chromatin structure. Prenatal alcohol exposure influences neuronal and astrocyte development, permanently altering brain connectivity. Prenatal alcohol exposure also alters chromatin structure through histone and DNA modifications. However, the data linking alcohol-induced differentiation changes with developmental alterations in chromatin structure remain to be elucidated. In the first part of this review, we discuss the sequence of chromatin structural changes involved in neural cell differentiation during normal development. We then discuss the effects of prenatal alcohol on developmental histone modifications and DNA methylation in the context of neurogenesis and astrogliogenesis. We attempt to synthesize the developmental literature with the FASD literature, proposing that alcohol-induced changes to chromatin structure account for altered neurogenesis and astrogliogenesis as well as altered neuron and astrocyte differentiation. Together these changes may contribute to the cognitive and behavioral abnormalities in FASD. Future studies using standardized alcohol exposure paradigms at specific developmental stages will advance the understanding of how chromatin structural changes impact neural cell fate and maturation in FASD.

Sajoy P. Varghese

Papers

High-dose prazosin for the treatment of post-traumatic stress disorder

Chromatin Switches during Neural Cell Differentiation and Their Dysregulation by Prenatal Alcohol Exposure

Early life stress as a risk factor for substance use disorders: Clinical and neurobiological substrates

Opioid use remits, depression remains.

Loperamide Addiction: Atypical Opioid Use Disorder Treated With Buprenorphine/Naloxone.