CRF Mediates Stress-Induced Pathophysiological High-Frequency Oscillations in Traumatic Brain Injury

Abstract

It is not known why there is increased risk to have seizures with increased anxiety and stress after traumatic brain injury (TBI). Stressors cause the release of corticotropin-releasing factor (CRF) both from the hypothalamic pituitary adrenal (HPA) axis and from CNS neurons located in the central amygdala and GABAergic interneurons. We have previously shown that CRF signaling is plastic, becoming excitatory instead of inhibitory after the kindling model of epilepsy. Here, using Sprague Dawley rats we have found that CRF signaling increased excitability after TBI. Following TBI, CRF type 1 receptor (CRFR 1 )-mediated activity caused abnormally large electrical responses in the amygdala, including fast ripples, which are considered to be epileptogenic. After TBI, we also found the ripple (120–250 Hz) and fast ripple activity (>250 Hz) was cross-frequency coupled with θ (3–8 Hz) oscillations. CRFR 1 antagonists reduced the incidence of phase coupling between ripples and fast ripples. Our observations indicate that pathophysiological signaling of the CRFR 1 increases the incidence of epileptiform activity after TBI. The use for CRFR 1 antagonist may be useful to reduce the severity and frequency of TBI associated epileptic seizures.

A Role for the Amygdala in Impairments of Affective Behaviors Following Mild Traumatic Brain Injury

“…The expression of CRF is increased in the amygdala following brain injury ( Narla et al, 2019 ; Tapp et al, 2019 ) and blockade of CRFR1 receptor 1 within the HPA axis attenuates post-traumatic stress and anxiety-like behaviors ( Kosari-Nasab et al, 2019 ). The activity of CRF in extrahypothalamic regions contributes to depression, anxiety, and fear-related behaviors ( Binder and Nemeroff, 2009 ; Sanford et al, 2017 ; Paretkar and Dimitrov, 2018 ).…”

“…The CeA contains CRF-positive neurons ( Rodaros et al, 2007 ), whereas the BLA contains numerous CRF receptor-positive projection neurons ( Roozendaal et al, 2002 ). Increased CRF in the BLA can impair memory consolidation ( Narla et al, 2019 ), whereas increased CRF in the nucleus accumbens leads to depressive behaviors likely by modulating extracellular acetylcholine ( Chen et al, 2012 ); CRF receptor 1 antagonists exhibit antidepressant activity ( Overstreet and Griebel, 2004 ). Neurons within the CeA that express CRF have been investigated for their role in perpetuating anxiety behaviors following chronic stress ( Paretkar and Dimitrov, 2018 ; Hupalo et al, 2019 ) and promote fear learning by regulating acquisition recall ( Sanford et al, 2017 ).…”

Corticotropin Releasing Factor Mediates KCa3.1 Inhibition, Hyperexcitability, and Seizures in Acquired Epilepsy

“…We found that a single dose of intraperitoneally injected ATM significantly reduced the 24 h average SRSs frequency by 41%, whereas a similar injection of the vehicle had no significant effect on this frequency. Interestingly, an anti-seizure effect of CRF 1 R antagonists was recently found also in EEG recordings from amygdala of rats subjected to traumatic brain injury, another type of insult causing TLE (Narla et al, 2019).…”

Pathophysiology of Pediatric Traumatic Brain Injury

“…Basic science and understanding of molecular mechanisms in this area are also lacking in pediatrics. While there are several studies that address pituitary dysfunction following TBI (151)(152)(153)(154)(155)(156)(157), these studies have only been done in adult rats. Greco et al, utilized an adolescent mild rTBI model to examine hypopituitarism following TBI.…”