Anxious behavior induces elevated hippocampal Cb2 receptor gene expression

Abstract

Anxiety is differentially expressed across a continuum of stressful/fearful intensity, influenced endocannabinoid systems and receptors. The hippocampus plays important roles in the regulation of affective behavior, emotion, and anxiety, as well as memory. Location of Cb1/Cb2 receptor action could be important in determining emotional valence, because while the dorsal hippocampus is involved in spatial memory and cognition, the ventral hippocampus has projections to the PFC, BNST, amygdala, and HPA axis, and is important for emotional responses to stress. During repeated social defeat in a Stress-Alternatives Model arena (SAM; an oval open field with escape portals only large enough for smaller mice), smaller C57BL6/N mice are subject to fear conditioning (tone = CS), and attacked by novel larger aggressive CD1 mice (US) over four daily (5 min) trials. Each SAM trial presents an opportunity for escape or submission, with stable behavioral responses established by the second day of interaction. Additional groups had access to a running wheel. Social aggression plus fear conditioning stimulates enhanced Cb2 receptor gene expression in the dorsal CA1, dorsal and ventral dentate gyrus subregions in animals displaying a submissive behavioral phenotype. Escape behavior is associated with reduced Cb2 expression in the dorsal CA1 region, with freezing and escape latency correlated with mRNA levels. Escaping and submitting animals with access to running wheels had increased Cb2 mRNA in dorsal DG/CA1. These results suggest that the Cb2 receptor system is rapidly induced during anxiogenic social interactions plus fear conditioning or exercise; with responses potentially adaptive for coping mechanisms.

Manual Hippocampal Subfield Segmentation Using High-Field MRI: Impact of Different Subfields in Hippocampal Volume Loss of Temporal Lobe Epilepsy Patients

“…The hippocampal formation, with its various subfields and connectivity, is a major hub for higher cognitive function, such as memory consolidation and learning, spatial navigation, and emotional expression/affective behavior ( 31 , 32 ). The role of the hippocampus in long-term, declarative memory formation was first established with studies in a TLE patient who underwent bilateral mesial temporal lobectomy and suffered, as a consequence, anterograde amnesia for explicit contents ( 33 , 34 ).…”

Cannabinoid Modulation of the Stressed Hippocampus

“…A recent study verified that high-levels of anxiety, when combined with aversive factors (fear conditioning or exercise), increases CB 2 receptor gene expression in the hippocampus. The opposite is also true: decreased anxiety (measured by escape response) was associated with reduced CB 2 gene expression (Robertson et al, 2017 ). In mice, overexpressing CB 2 receptors decreases anxiety-like behaviors, which is partially explained by changes in hippocampal GABA A receptors (García-Gutiérrez and Manzanares, 2011 ).…”

Learning and CRF-Induced Indecision during Escape and Submission in Rainbow Trout during Socially Aggressive Interactions in the Stress-Alternatives Model

“…Also BDNF, TrK B , AMPA receptor subunit GluA 1 genes exhibit greater expression in trout dorsolateral pallium (Dl, homologous to hippocampus) (Carpenter et al, 2009b ). Gene expression may also be predictive of the submissive (Stay) phenotype, in which SAM interaction plus FC stimulates elevated levels of cannabinoid 2 receptor (Cb 2 ) in both dorsal and ventral hippocampus (Robertson et al, 2017 ). Interestingly, though both Stay and Escape phenotypes receive significant levels of aggression, neither the quantity nor the intensity of attack determines which behavioral phenotype is adopted (Figure 2 ), and therefore differences in hormone and gene expression in those groups are determined by the choice of behavioral response (Prince et al, 2015 ).…”

“…In many vertebrate populations, understanding behaviors that predict susceptibility to stress, coincident with neuroplastic changes that result in heightened or reduced stress responsiveness, may help identify at-risk populations for behavioral inhibition, and humans vulnerable to anxiety, depression, and PTSD. Our recently developed SAM concept and apparatus was designed to probe the highly evolutionarily conserved decision-making that occurs during social stress and produces alternatives in behavior, and therefore reveals behavioral and neural indicators (Smith et al, 2014 , 2016 ; Robertson et al, 2015 , 2017 ).…”