Franks, H. T. | Search bioRxiv

bioRxiv2023

Locus Coeruleus Norepinephrine Neurons Facilitate Orbitofrontal Cortex Remapping and Behavioral Flexibility

To guide behavior, brain regions such as the orbitofrontal cortex (OFC) retain complex information about current tasks and expected outcomes in cellular representations referred to as cognitive maps. When actions produce undesirable results, OFC cognitive maps must update to promote behavioral change. Here, we show that this remapping is driven by the locus coeruleus (LC), a small brainstem nucleus that contains most of the brains norepinephrine (NE)-releasing neurons. In a task that tests behavioral flexibility in rodents, LC-NE activity correlated with task acuity and altered depending on trial outcome. Silencing LC neurons caused perseverative behavior and impeded cognitive remapping in OFC, while enhancing LC activity disrupted the ability of new maps to stabilize. These findings reveal a novel role for bidirectional LC-NE signaling in regulation of OFC cognitive map stability and promotion of flexible behavior that differs from the traditional function of this circuit as a global arousal signal.

neuroscience↗

bioRxiv2022

Divergent risky decision-making and impulsivity behaviors in two Lewis substrains of rats with low genetic difference

Substance use disorder (SUD) is associated with a cluster of cognitive disturbances that engender vulnerability to ongoing drug seeking and relapse. Two of these endophenotypes--risky decision-making and impulsivity--are amplified in individuals with substance use disorder and are augmented by repeated exposure to illicit drugs. Identifying genetic factors underlying variability in these traits is critical for early identification, prevention, and treatment of SUD-vulnerable individuals. Here, we compared risky decision-making and different facets of impulsivity between two fully inbred substrains of Lewis rats--LEW/NCrl and LEW/NHsd. We performed whole genome sequencing of both substrain to identify almost all relevant variants. We observed substantial differences in risky decision-making and impulsive behaviors. Relative to LEW/HHsd, the LEW/NCrl substrain accepts higher risk options in a decision-making task and higher rates of premature responses in the differential reinforcement of low rates of responding (DRL) task. These phenotypic differences were more pronounced in females than males. We defined a total of [~]9,000 polymorphisms between these substrains at 40X whole genome short-read coverage. Roughly half of variants are located within a single 1.5 Mb region of chromosome 8, but none impact protein-coding regions. In contrast, other variants are widely distributed, and of these 38 are predicted to cause protein-coding variants. In conclusion, Lewis rat substrains differ significantly in risk-taking and impulsivity and only a small number of easily mapped variants are likely to be causal. Sequencing combined with a reduced complexity cross (RCC) should enable identification of one or more variants underlying multiple complex addiction-relevant traits.

genomics↗