Selective Functional Interaction Between the Lateral Habenula and Hippocampus During Different Tests of Response Flexibility

Abstract

The lateral habenula (LHb) has been shown to play critical roles in a variety of appetitive tasks (e.g., spatial memory and object recognition) that require animals to flexibly respond to changing task conditions. These types of tasks are known to be dependent on hippocampus (HPC) and/or medial prefrontal cortex (mPFC), suggesting that the LHb contributes to the limbic memory circuit. Here we provide new evidence that the LHb and HPC play distinct but complimentary roles in tasks that require flexible responding to changing task conditions. Experiment 1 tested whether the LHb is needed for the performance of a HPC-dependent maze-based spatial delayed alternation task. The importance of interactions between the LHb and HPC to accomplish the same spatial delayed alternation task was tested in Experiment 2 where the LHb and HPC were disconnected both ipsilaterally and contralaterally. Experiment 3 tested LHb’s involvement in a standard behavioral economic task that requires flexible responding (maze-based delayed discounting), a task previously shown to rely on HPC. Results of Experiment 1, revealed that LHb inactivation impairs spatial delayed alternation during asymptotic performance but not during initial learning. Importantly, working memory did not appear to be affected as performance remained above chance levels both during initial learning and asymptotic testing. Experiment 2 showed that ipsilateral and contralateral disconnection of the LHb and HPC led to impaired performance on the spatial delayed alternation task. Impairments were not observed after unilateral inactivation of only one structure. Results of Experiment 3 were similar to our previous report of the effects of HPC inactivation: LHb inactivation impaired delayed discounting. All effects could not be accounted for by changes in reward magnitude discrimination, reward location per se, or sex of the animal. These findings, combined with other recent publications confirms and extends our working hypothesis that the LHb enables adaptive and flexible responding, particularly when established rules must be flexibly applied on a trial by trial basis. Since there are no known direct anatomical connections between LHb and HPC, future research is needed to understand how these structures communicate to enable flexible and rapid responding.

A Machine Learning Approach for Detecting Vicarious Trial and Error Behaviors

“…Food restricted (85% of body weight) Long Evans rats ( n = 9, Charles River Laboratories) were trained on a previously described spatial delayed alternation task (SDA) task (Baker et al, 2019 ; Kidder et al, 2021 ). Briefly, sessions were run on an elevated plus maze (black plexiglass arms, 58 cm long × 5.5 cm wide, elevated 80 cm from floor), with moveable arms and reward feeders controlled by custom LabView 2016 software (National Instruments, Austin, TX, USA).…”

A selective role for the mPFC during choice and deliberation, but not spatial memory retention over short delays

“…Two optic fibers (one per hemisphere) were implanted bilaterally into the mPFC. Training procedures were similar to those previously published (Baker, Rao, Rivera, Garcia, & Mizumori, 2019). Briefly, prior to surgery, rats were food restricted to 85% of their free feeding weight.…”

Independence of Cued and Contextual Components of Fear Conditioning is Gated by the Lateral Habenula

“…Contextual FC is also blocked by pharmacological inactivation or artificial excitation of the LHb during whole training. It has been proposed elsewhere that the LHb influences context encoding through a functional interaction with the hippocampus (Baker et al, 2019;Goutagny et al, 2013). That hypothesis has received support from physiological data generated by other authors and us showing that firing of the neurons of the LHb is synchronized with hippocampal theta rhythm (Aizawa et al, 2013;Bertone-Cueto et al, 2020;Goutagny et al, 2013).…”