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The mechanisms that confer cognitive resilience to Alzheimer's Disease (AD) are not fully understood. Here, we describe a neural circuit mechanism underlying this resilience in a familial AD mouse model. In the prodromal disease stage, interictal epileptiform spikes (IESs) emerge during anesthesia in the CA1 and mPFC regions, leading to working memory disruptions. These IESs are driven by inputs from the thalamic nucleus reuniens (nRE). Indeed, tonic deep brain stimulation of the nRE (tDBS-nRE) effectively suppresses IESs and restores firing rate homeostasis under anesthesia, preventing further impairments in nRE-CA1 synaptic facilitation and working memory. Notably, applying tDBS-nRE during the prodromal phase in young APP/PS1 mice mitigates age-dependent memory decline. The IES rate during anesthesia in young APP/PS1 mice correlates with later working memory impairments. These findings highlight the nRE as a central hub of functional resilience and underscore the clinical promise of DBS in conferring resilience to AD pathology by restoring circuit-level homeostasis., (© 2023. The Author(s).)

Spontaneous spiking activity depends on intrinsic excitability and synaptic input. Historically, synaptic activity has been mostly studied ex vivo . Here, we describe a versatile and robust protocol to record field excitatory postsynaptic potentials (fEPSPs) in behaving rodents. The protocol allows estimating the input-output relationship of a specific pathway, short-term and long-term plasticity, and their modulation by pharmacological or pharmacogenetic interventions and behavioral states. However, experimenters must be aware of the protocol's specificity and interpret results with care. For complete details on the use and execution of this profile, please refer to Styr et al. (2019)., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)

Dysregulated homeostasis of neural activity has been hypothesized to drive Alzheimer's disease (AD) pathogenesis. AD begins with a decades-long presymptomatic phase, but whether homeostatic mechanisms already begin failing during this silent phase is unknown. We show that before the onset of memory decline and sleep disturbances, familial AD (fAD) model mice display no deficits in CA1 mean firing rate (MFR) during active wakefulness. However, homeostatic down-regulation of CA1 MFR is disrupted during non-rapid eye movement (NREM) sleep and general anesthesia in fAD mouse models. The resultant hyperexcitability is attenuated by the mitochondrial dihydroorotate dehydrogenase (DHODH) enzyme inhibitor, which tunes MFR toward lower set-point values. Ex vivo fAD mutations impair downward MFR homeostasis, resulting in pathological MFR set points in response to anesthetic drug and inhibition blockade. Thus, firing rate dyshomeostasis of hippocampal circuits is masked during active wakefulness but surfaces during low-arousal brain states, representing an early failure of the silent disease stage., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the rate of major anomalies after first trimester (T1)-metformin exposure., Design: Comparative, observational cohort study done at the Israeli Teratology Information Service between 2000 and 2013., Results: 170 T1-metformin-exposed pregnancies [119 for diabetes and 51 for polycystic ovary syndrome (PCOS)] were prospectively followed-up and compared with 93 pregnancies of T1-insulin treated women and 530 non-teratogenic exposed (NTE) pregnancies. The differences in the rate of major anomalies excluding genetic/cytogenetic, and spontaneously resolved cardiovascular anomalies were not significant [4.4% (2/45) - metformin-PCOS, 1.1% (1/90) - metformin-diabetes, 2.5% (2/80) - insulin, and 1.7% (9/519) - NTE; OR adj metformin / NTE 1.77; 95% CI 0.45-7.01; OR adj insulin / NTE 1.69; 95% CI 0.35-8.11]. The rate of Cesarean section was higher in both the metformin-diabetes 51/90 (56.7%) and insulin 45/79 (57.0%) groups compared with the NTE group [138/503 (27.4%)]., Conclusion: Metformin-T1-exposure per se is not associated with an increased risk of major anomalies., (Copyright © 2018 Elsevier Inc. All rights reserved.)