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Background: Anxiety and social withdrawal are highly prevalent among patients with Alzheimer's disease (AD). However, the neural circuit mechanisms underlying these symptoms remain elusive, and there is a need for effective prevention strategies. Objective: This study aims to elucidate the neural circuitry mechanisms underlying social anxiety in AD. Methods: We utilized 5xFAD mice and conducted a series of experiments including optogenetic manipulation, Tandem Mass Tag-labeled proteome analysis, behavioral assessments, and immunofluorescence staining. Results: In 5xFAD mice, we observed significant amyloid-β (Aβ) accumulation in the anterior part of basolateral amygdala (aBLA). Behaviorally, 6-month-old 5xFAD mice displayed excessive social avoidance during social interaction. Concurrently, the pathway from aBLA to ventral hippocampal CA1 (vCA1) was significantly activated and exhibited a disorganized firing patterns during social interaction. By optogenetically inhibiting the aBLA-vCA1 pathway, we effectively improved the social ability of 5xFAD mice. In the presence of Aβ accumulation, we identified distinct changes in the protein network within the aBLA. Following one month of administration of Urolithin A (UA), we observed significant restoration of the abnormal protein network within the aBLA. UA treatment also attenuated the disorganized firings of the aBLA-vCA1 pathway, leading to an improvement in social ability. Conclusions: The aBLA-vCA1 circuit is a vulnerable pathway in response to Aβ accumulation during the progression of AD and plays a crucial role in Aβ-induced social anxiety. Targeting the aBLA-vCA1 circuit and UA administration are both effective strategies for improving the Aβ-impaired social ability. [ABSTRACT FROM AUTHOR]

Generalization is a fundamental cognitive ability of organisms to deal with the uncertainty in real-world situations. Excessive fear generalization and impaired reward generalization are closely related to many psychiatric disorders. However, the neural circuit mechanism for reward generalization and its role in anxiety-like behaviours remain elusive. Here, we found a robust activation of calbindin 1-neurons (Calb 1) in the posterior basolateral amygdala (pBLA), simultaneous with reward generalization to an ambiguous cue after reward conditioning in mice. We identify the infralimbic medial prefrontal cortex (IL) to the pBLACalb1 (Calb 1 neurons in the pBLA) pathway as being involved in reward generalization for the ambiguity. Activating IL–pBLA inputs strengthens reward generalization and reduces chronic unpredictable mild stress-induced anxiety- and depression-like behaviours in a manner dependent on pBLACalb1 neuron activation. These findings suggest that the IL–pBLACalb1 circuit could be a target to promote stress resilience via reward generalization and consequently ameliorate anxiety- and depression-like behaviours. The neural mechanisms for reward generalization are not fully understood. Here the authors investigate the role of posterior basolateral amygdala calbindin-expressing cells in modulating behavioural responses related to reward and aversion. [ABSTRACT FROM AUTHOR]

The basolateral amygdala (BLA) and ventral hippocampal CA1 (vCA1) are cellularly and functionally diverse along their anterior–posterior and superficial-deep axes. Here, we find that anterior BLA (aBLA) and posterior BLA (pBLA) innervate deep-layer calbindin1-negative (Calb1−) and superficial-layer calbindin1-positive neurons (Calb1+) in vCA1, respectively. Photostimulation of pBLA–vCA1 inputs has an anxiolytic effect in mice, promoting approach behaviours during conflict exploratory tasks. By contrast, stimulating aBLA–vCA1 inputs induces anxiety-like behaviour resulting in fewer approaches. During conflict stages of the elevated plus maze task vCA1Calb1+ neurons are preferentially activated at the open-to-closed arm transition, and photostimulation of vCA1Calb1+ neurons at decision-making zones promotes approach with fewer retreats. In the APP/PS1 mouse model of Alzheimer's disease, which shows anxiety-like behaviour, photostimulating the pBLA–vCA1Calb1+ circuit ameliorates the anxiety in a Calb1-dependent manner. These findings suggest the pBLA–vCA1Calb1+ circuit from heterogeneous BLA–vCA1 connections drives approach behaviour to reduce anxiety-like behaviour. Projections from the anterior and posterior basolateral amygdala (pBLA) to the ventral hippocampus CA1 (vCA1) are heterogenous. Here the authors show that activating the pathway from pBLA to vCA1 calbindin 1 positive neurons has an anxiolytic effect in approach-avoidance tasks in mice. [ABSTRACT FROM AUTHOR]