Russ, A. N. | bioRxiv Science

bioRxiv2022

Hyperactive somatostatin interneurons near amyloid plaque and cell-type-specific firing deficits in a mouse model of Alzheimer's disease

Alzheimers disease (AD) is characterized by synaptic loss and neuronal network dysfunction. These network deficits are mediated by early alterations in neuronal firing rates that coincide with amyloid plaque accumulation. Mounting evidence supports that inhibitory networks are impaired in AD, but the mechanisms driving these inhibitory deficits are poorly understood. Here we use in vivo multiphoton calcium imaging to determine the relationship between amyloid accumulation and the spontaneous activity of excitatory neurons and inhibitory interneurons in an APP/PS1 mouse model of Alzheimers disease. We show that somatostatin-expressing (SOM) interneurons are hyperactive, while parvalbumin-expressing interneurons are hypoactive in APP/PS1 mice. Only SOM interneuron hyperactivity correlated with proximity to amyloid plaque. These inhibitory deficits were accompanied by decreased excitatory neurons activity and decreased pairwise activity correlations in APP/PS1 mice. Our study identifies cell-specific interneuronal firing deficits driven by amyloid pathology in APP/PS1 mice and provides new insights for targeting inhibitory circuits in Alzheimers disease.

neuroscience↗

bioRxiv2020

The nucleus accumbens core is necessary to scale fear to degree of threat

Fear is adaptive when the level of the response rapidly scales to degree of threat. Using a discrimination procedure consisting of danger, uncertainty and safety cues, we have found rapid fear scaling (within two seconds of cue presentation) in male rats. Here we examined a possible role for the nucleus accumbens core (NAcc) in the acquisition and expression of fear scaling. In experiment 1, male Long Evans rats received bilateral sham or neurotoxic NAcc lesions, recovered and underwent fear discrimination. NAcc-lesioned rats were generally impaired in scaling fear to degree of threat, and specifically impaired in rapid uncertainty-safety discrimination. In experiment 2, male Long Evans rats received NAcc transduction with halorhodopsin or a control fluorophore. After fear scaling was established, the NAcc was illuminated during cue or control periods. NAcc-halorhodopsin rats receiving cue illumination were specifically impaired in rapid uncertainty-safety discrimination. The results reveal a general role for the NAcc in scaling fear to degree of threat, and a specific role in rapid discrimination of uncertain threat and safety. Significance StatementRapidly discriminating cues for threat and safety is essential for survival and impaired threat-safety discrimination is a hallmark of stress and anxiety disorders. In two experiments, we induced nucleus accumbens core (NAcc) dysfunction in rats receiving fear discrimination consisting of cues for danger, uncertainty and safety. Permanent NAcc dysfunction, via neurotoxic lesion, generally disrupted the ability to scale fear to degree of threat, and specifically impaired one component of scaling: rapid discrimination of uncertain threat and safety. Reversible NAcc dysfunction, via optogenetic inhibition, specifically impaired rapid discrimination of uncertain threat and safety. The results reveal that the NAcc is essential to scale fear to degree of threat, and is a plausible source of dysfunction in stress and anxiety disorders.

neuroscience↗