Predator Stress-Induced CRF Release Causes Enduring Sensitization of Basolateral Amygdala Norepinephrine Systems that Promote PTSD-Like Startle Abnormalities.
The neurobiology of post-traumatic stress disorder (PTSD) remains unclear. Intense stress promotes PTSD, which has been associated with exaggerated startle and deficient sensorimotor gating. Here, we examined the long-term sequelae of a rodent model of traumatic stress (repeated predator exposure) on amygdala systems that modulate startle and prepulse inhibition (PPI), an operational measure of sensorimotor gating. We show in rodents that repeated psychogenic stress (predator) induces long-lasting sensitization of basolateral amygdala (BLA) noradrenergic (NE) receptors (α1) via a corticotropin-releasing factor receptor 1 (CRF-R1)-dependent mechanism, and that these CRF1 and NE α1 receptors are highly colocalized on presumptive excitatory output projection neurons of the BLA. A profile identical to that seen with predator exposure was produced in nonstressed rats by intra-BLA infusions of CRF (200 ng/0.5 μl), but not by repeated NE infusions (20 μg/0.5 μl). Infusions into the adjacent central nucleus of amygdala had no effect. Importantly, the predator stress- or CRF-induced sensitization of BLA manifested as heightened startle and PPI deficits in response to subsequent subthreshold NE system challenges (with intra-BLA infusions of 0.3 μg/0.5 μl NE), up to 1 month after stress. This profile of effects closely resembles aspects of PTSD. Hence, we reveal a discrete neural pathway mediating the enhancement of NE system function seen in PTSD, and we offer a model for characterizing potential new treatments that may work by modulating this BLA circuitry.


CONCLUSIONS
The present findings reveal a novel and discrete neural substrate that could underlie certain core deficits (startle and prepulse inhibition) that are observed in post-traumatic stress disorder (PTSD). It is shown here that repeated exposure to a rodent model of traumatic stress (predator exposure) produces a long-lasting sensitization of basolateral amygdala noradrenergic substrates [via a corticotropin-releasing factor (CRF)-dependent mechanism] that regulate startle, which is exaggerated in PTSD. Moreover, it is demonstrated that the sensitized noradrenergic receptors colocalize with CRF1 receptors on output projection neurons of the basolateral amygdala. Hence, this stress-induced sensitization of noradrenergic receptors on basolateral nucleus efferents has wide-ranging implications for the numerous deleterious sequelae of trauma exposure that are seen in multiple psychiatric illnesses, including PTSD.
Neuroscience Training Program, University of Wisconsin-Madison, Madison, Wisconsin 53719.
Abha K
http://orcid.org/0000-0002-5596-8735
AK
Rajbhandari
Department of Psychiatry and Neuroscience Training Program, University of Wisconsin-Madison, Madison, Wisconsin 53719 vbakshi@wisc.edu babaldo@wisc.edu.
Brian A
BA
Baldo
Department of Psychiatry and Neuroscience Training Program, University of Wisconsin-Madison, Madison, Wisconsin 53719 vbakshi@wisc.edu babaldo@wisc.edu.
Vaishali P
VP
Bakshi
D000161:Acoustic Stimulation; D000704:Analysis of Variance; D000818:Animals; D066272:Basolateral Nuclear Complex / Q000187:drug effects / Q000378:metabolism*; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism* / Q000494:pharmacology; D005289:Ferrets; D005968:Glutamate Decarboxylase / Q000378:metabolism; D008297:Male; D009638:Norepinephrine / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011941:Receptors, Adrenergic / Q000378:metabolism; D018019:Receptors, Corticotropin-Releasing Hormone / Q000378:metabolism; D013216:Reflex, Startle / Q000187:drug effects / Q000502:physiology*; D013313:Stress Disorders, Post-Traumatic / Q000473:pathology*; D013315:Stress, Psychological / Q000473:pathology*; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism; D000099052:CRF Receptor, Type 1
D011941:Receptors, Adrenergic; D018019:Receptors, Corticotropin-Releasing Hormone; D005680:gamma-Aminobutyric Acid; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone; D005968:Glutamate Decarboxylase; D009638:Norepinephrine
corticotropin-releasing factor; corticotropin-releasing hormone; noradrenergic; prepulse inhibition; schizophrenia; sensorimotor gating