Corticotropin-Releasing Factor in the Norepinephrine Nucleus, Locus Coeruleus, Facilitates Behavioral Flexibility

Abstract

Corticotropin-releasing factor (CRF), the stress-related neuropeptide, acts as a neurotransmitter in the brain norepinephrine nucleus, locus coeruleus (LC), to activate this system during stress. CRF shifts the mode of LC discharge from a phasic to a high tonic state that is thought to promote behavioral flexibility. To investigate this, the effects of CRF administered either intracerebroventricularly (30-300 ng, i.c.v.) or directly into the LC (intra-LC; 2-20 ng) were examined in a rat model of attentional set shifting. CRF differentially affected components of the task depending on dose and route of administration. Intracerebroventricular CRF impaired intradimensional set shifting, reversal learning, and extradimensional set shifting (EDS) at different doses. In contrast, intra-LC CRF did not impair any aspect of the task. The highest dose of CRF (20 ng) facilitated reversal learning and the lowest dose (2 ng) improved EDS. The dose-response relationship for CRF on EDS performance resembled an inverted U-shaped curve with the highest dose having no effect. Intra-LC CRF also elicited c-fos expression in prefrontal cortical neurons with an inverted U-shaped dose-response relationship. The number of c-fos profiles was positively correlated with EDS performance. Given that CRF excites LC neurons, the ability of intra-LC CRF to activate prefrontal cortical neurons and facilitate EDS is consistent with findings implicating LC-norepinephrine projections to medial prefrontal cortex in this process. Importantly, the results suggest that CRF release in the LC during stress facilitates shifting of attention between diverse stimuli in a dynamic environment so that the organism can adapt an optimal strategy for coping with the challenge.

Corticotropin-Releasing Factor Acting at the Locus Coeruleus Disrupts Thalamic and Cortical Sensory-Evoked Responses

“…We estimated CRF concentrations at the LC following diffusion from the peri-LC infusion site using the upper bounds estimate (Newton's inverse square law) and with more realistic models that account for the diffusion coefficient of CRF, volume fraction, and tortuosity (Nicholson, 2001;Shorten and Wall, 2001). These analyses indicate that our peri-LC infusions resulted in CRF concentrations within the LC nucleus nearly identical to previous studies that directly infused CRF within the LC (Curtis et al, 1997;Snyder et al, 2012). Specifically, following 300 ng CRF infusions, maximal estimates of CRF were 30 and 3 ng at distances of 32 and 110 mm from the infusion needle, respectively, using the inverse square method.…”

Corticotropin-releasing Factor in the Rat Dorsal Raphe Nucleus Promotes Different Forms of Behavioral Flexibility Depending on Social Stress History

“…The ability of moderate levels of CRF in the DRN to facilitate strategy set-shifting in the present study is reminiscent of the improvement of attention set shifting by similar levels of CRF in the LC (Snyder et al, 2012). Together the results suggest that acute stress can facilitate this form of cognitive flexibility through parallel actions of CRF in the LC and DRN and this is an adaptive cognitive response to the stressor.…”

Stress facilitates late reversal learning using a touchscreen-based visual discrimination procedure in male Long Evans rats

“…Graybeal et al [11] found that injection of brain-derived neurotrophic factor (BDNF) directly into the vmPFC following stress is sufficient to prevent facilitation of reversal learning. In addition, a high dose of corticotropin-releasing factor (CRF) injected into the locus coeruleus facilitates reversal learning in rats [27]. Stress-induced changes in neurotransmitters such as glutamate, dopamine, and serotonin may also play a role in reversal learning facilitation [14,15,28].…”