Cell type-specific modifications of corticotropin-releasing factor (CRF) and its type 1 receptor (CRF1) on startle behavior and sensorimotor gating. (March 2015)

• Record Type: Journal Article
• Authors: Flandreau, Elizabeth; Risbrough, Victoria; Lu, Ailing; Ableitner, Martin; Geyer, Mark A.; Holsboer, Florian; Deussing, Jan M.
• Is Part Of: Psychoneuroendocrinology. Volume 53(2015:Mar.)
• Page Start: 16
• Page End: 28
• Publication Date: 2015-03
• Subjects: CRF -- CRH -- Acoustic startle -- Prepulse inhibition -- PTSD; Psychoneuroendocrinology -- Periodicals; Endocrinology -- Periodicals; Neurology -- Periodicals; Psychiatry -- Periodicals; Neuropsychoendocrinologie -- Périodiques; 616.8
• DOI: 10.1016/j.psyneuen.2014.12.005
• Languages: English
• ISSNs: 0306-4530

Abstract

Highlights: CRF overexpression in neurons increases startle and reduces PPI via CRF1 receptor. Forebrain CRF1 receptor is not necessary for CRF or stress effects on startle. CRF overexpression limited to inhibitory neurons decreases startle. The specific neural source of CRF drives specific startle plasticity phenotypes. Abstract: The corticotropin-releasing factor (CRF) family of peptides and receptors coordinates the mammalian endocrine, autonomic, and behavioral responses to stress. Excessive CRF production has been implicated in the etiology of stress-sensitive psychiatric disorders such as posttraumatic stress disorder (PTSD), which is associated with alterations in startle plasticity. The CRF family of peptides and receptors mediate acute startle response changes during stress, and chronic CRF activation can induce startle abnormalities. To determine what neural circuits modulate startle in response to chronic CRF activation, transgenic mice overexpressing CRF throughout the central nervous system (CNS; CRF-COE CNS ) or restricted to inhibitory GABAergic neurons (CRF-COE GABA ) were compared across multiple domains of startle plasticity. CRF overexpression throughout the CNS increased startle magnitude and reduced ability to inhibit startle (decreased habituation and decreased prepulse inhibition (PPI)), similar to previous reports of exogenous effects of CRF. Conversely, CRF overexpression confined to inhibitory neurons decreased startle magnitude but had no effect on inhibitory measures. Acute CRF receptor 1 (CRF1 ) antagonist treatment attenuated only the effects on startle induced by CNS-specific CRF overexpression. Specific deletion of CRF1 receptors from forebrain principal neurons failed to alter the effects of exogenous CRF or stress on startle, suggesting that these CRF1 expressing neurons are not required for CRF-induced changes in startle behaviors. These data indicate that the effects of CRF activation on startle behavior utilize an extensive neural circuit that includes both forebrain and non-forebrain regions. Furthermore, these findings suggest that the neural source of increased CRF release determines the startle phenotype elicited. It is conceivable that this may explain why disorders characterized by increased CRF in cerebrospinal fluid (e.g. PTSD and major depressive disorder) have distinct symptom profiles in terms of startle reactivity.