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

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-COECNS) or restricted to inhibitory GABAergic neurons (CRF-COEGABA) 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.

Vesicular monoamine transporter 2 mediates fear behavior in mice

“…Startle assays were performed as described in Flandreau et al Briefly, mice underwent multiple sessions in order to assess startle magnitude and prepulse inhibition. Because mice that are physically heavier produce a more robust startle response and VMAT2‐LO mice tend to be physically smaller than VMAT2‐WT and ‐HI mice, each startle response was normalized to that mouse's average startle response to a 120 dB tone.…”

Role of environmental stressors in determining the developmental outcome of neonatal anesthesia

“…In addition, the etomidate-caused inhibition of 11-β-hydroxylase increases substrate availability for synthesis of GABAergic neuroactive steroids, which by enhancing GABA A R-mediated depolarization/stimulation in the hypothalamus of neonatal rats may further increase production of corticotropin-releasing hormone (CRH) (Kaminski and Rogawski MA, 2001). An increase in CRH production is not only a crucial initial step in the activation of the LHPA axis by stress, but may also contribute to a number of neurodevelopmental abnormalities by acting outside of the LHPA axis (Toth et al , 2014; Flandreau et al , 2015; Zhang et al , 2016). …”

High and Low Threshold for Startle Reactivity Associated With PTSD Symptoms but Not PTSD Risk: Evidence From a Prospective Study of Active Duty Marines

“…PTSD patients exhibit increased CRF levels in cerebrospinal fluid and increased glucocorticoid sensitivity . Moderate CRF and glucocorticoid levels induce increased startle whereas high doses induce reduced startle reactivity CRF‐induced inhibition or potentiation of startle also depend on neural sources of CRF hypersignaling . Future research is needed to determine if these neural circuits and signaling pathways are linked to different startle thresholds.…”

“…[69] Moderate CRF and glucocorticoid levels induce increased startle whereas high doses induce reduced startle reactivity [70][71][72][73] CRF-induced inhibition or potentiation of startle also depend on neural sources of CRF hypersignaling. [74] Future research is needed to determine if these neural circuits and signaling pathways are linked to different startle thresholds. Understanding the neurobiological mechanisms influencing startle threshold might help identify separate functional pathologies across PTSD and other anxiety disorders.…”