Bidirectional Control of Anxiety-Related Behaviors in Mice: Role of Inputs Arising from the Ventral Hippocampus to the Lateral Septum and Medial Prefrontal Cortex

Abstract

Anxiety is an adaptive response to potentially threatening situations. Exaggerated and uncontrolled anxiety responses become maladaptive and lead to anxiety disorders. Anxiety is shaped by a network of forebrain structures, including the hippocampus, septum, and prefrontal cortex. In particular, neural inputs arising from the ventral hippocampus (vHPC) to the lateral septum (LS) and medial prefrontal cortex (mPFC) are thought to serve as principal components of the anxiety circuit. However, the role of vHPC-to-LS and vHPC-to-mPFC signals in anxiety is unclear, as no study has directly compared their behavioral contribution at circuit level. We targeted LS-projecting vHPC cells and mPFC-projecting vHPC cells by injecting the retrogradely propagating canine adenovirus encoding Cre recombinase into the LS or mPFC, and injecting a Cre-responsive AAV (AAV8-hSyn-FLEX-hM3D or hM4D) into the vHPC. Consequences of manipulating these neurons were examined in well-established tests of anxiety. Chemogenetic manipulation of LS-projecting vHPC cells led to bidirectional changes in anxiety: activation of LS-projecting vHPC cells decreased anxiety whereas inhibition of these cells produced opposite anxiety-promoting effects. The observed anxiety-reducing function of LS-projecting cells was in contrast with the function of mPFC-projecting cells, which promoted anxiety. In addition, double retrograde tracing demonstrated that LS- and mPFC-projecting cells represent two largely anatomically distinct cell groups. Altogether, our findings suggest that the vHPC houses discrete populations of cells that either promote or suppress anxiety through differences in their projection targets. Disruption of the intricate balance in the activity of these two neuron populations may drive inappropriate behavioral responses seen in anxiety disorders.

Chronic Fluoxetine Induces Activity Changes in Recovery From Poststroke Anxiety, Depression, and Cognitive Impairment

“…The lateral septum receives dense 5-HT innervation and is particularly sensitive to SSRIs [60,61]. In PSD mice, chronic FLX and combination treatments but not exercise alone induced GABAergic FosB + cells, consistent with a chronic anxiolytic role for septal interneurons [62][63][64]. A Fig.…”

Survival circuits and risk assessment

“…However, this theta-rhythmicity may be more related to the approach or withdrawal that follows RA than it is to RA itself [46]. Conversely, a distinct population of ventral hippocampal cells that targets the lateral septum rather than the medial PFC inhibits anxiety-related behavior, perhaps as a form of negative feedback [44]. In contrast to the positive role of the basolateral, the basomedial amygdala appears to mediate suppression by the ventromedial PFC of a wide range of fear-and anxiety-related responses [47**].…”

“…Interestingly, the key output from the amygdala in its control of PAG-based RA behavior is ascending: to medial PFC either directly [41] or relayed [42] via the ventral hippocampus [43,44]. This transfer, like many other processes [45*], depends on theta-frequency synchrony [42].…”

Double dissociation of learned approach–avoidance conflict processing and spatial pattern separation along the dorsoventral axis of the dentate gyrus

“…Converging human and animal evidence suggests that the ventral hippocampus (HPC) (anterior HPC in humans) is critical for the expression of affective behaviors, particularly in the detection and resolution of approach–avoidance conflict, which evokes anxiogenic responses (Bach et al, 2014; Fanselow & Dong, ; Ito & Lee, ; O'Neil et al, ; Strange, Witter, Lein, & Moser, ). Much of this evidence comes from tasks that elicit approach–avoidance conflict without prior learning such as the elevated plus maze (EPM), light–dark box, and open field, which are commonly used in rodent studies as tests of anxiety and require the animal to respond based on an innate drive for exploration and an innate aversion to spaces that leave them open to predation (Bannerman et al, ; Kheirbek et al, ; Kjelstrup et al, ; Parfitt et al, ; Trivedi, ; Weeden, Roberts, Kamm, & Kesner, ). More recently, it has also been demonstrated that ventral HPC‐sensitive approach–avoidance conflict can also be elicited by presenting rodents with learned/conditioned stimuli that predict the availability of both positive and negative outcomes (Schumacher et al, ; Schumacher, Vlassov, & Ito, ), which may hold more translational value as real‐life approach–avoidance conflict scenarios usually involve learned stimuli (Ito & Lee, ).…”