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Innate defensive behaviors are essential for species survival. While these behaviors start to develop early in an individual's life, there is still much to be understood about how they evolve with advancing age. Considering that aging is often accompanied by various cognitive and physical declines, we tested the hypothesis that innate fear behaviors and underlying cerebral mechanisms are modified by aging. In our study we investigated this hypothesis by examining how aged mice respond to a looming visual threat compared to their younger counterparts. Our findings indicate that aged mice exhibit a different fear response than young mice when facing this imminent threat. Specifically, unlike young mice, aged mice tend to predominantly display freezing behavior without seeking shelter. Interestingly, this altered behavioral response in aged mice is linked to a distinct pattern of functional brain connectivity compared to young mice. Notably, our data highlights a lack of a consistent brain activation following the fear response in aged mice, suggesting that innate defensive behaviors undergo changes with aging., (© 2024. The Author(s).)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Fluorescence lifetime imaging microscopy (FLIM) opens new dimensions for highly multiplexed imaging in live cells and organisms using differences in fluorescence lifetime to distinguish spectrally identical fluorescent probes. Here, a set of fluorescence-activating and absorption-shifting tags (FASTs) capable of modulating the fluorescence lifetime of embedded fluorogenic 4-hydroxybenzylidene rhodanine (HBR) derivatives is described. It is shown that changes in the FAST protein sequence can vary the local environment of the chromophore and lead to significant changes in fluorescence lifetime. These fluorescence lifetime-modulating tags enable multiplexed imaging of up to three targets in one spectral channel using a single HBR derivative in live cells and live zebrafish larvae. The combination of fluorescence lifetime multiplexing with spectral multiplexing allows to successfully image six targets in live cells, opening great prospects for multicolor fluorescence lifetime multiplexing., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

In most models of neuronal plasticity and memory, dopamine is thought to promote the long-term maintenance of Long-Term Potentiation (LTP) underlying memory processes, but not the initiation of plasticity or new information storage. Here, we used optogenetic manipulation of midbrain dopamine neurons in male DAT::Cre mice, and discovered that stimulating the Schaffer collaterals - the glutamatergic axons connecting CA3 and CA1 regions - of the dorsal hippocampus concomitantly with midbrain dopamine terminals within a 200 millisecond time-window triggers LTP at glutamatergic synapses. Moreover, we showed that the stimulation of this dopaminergic pathway facilitates contextual learning in awake behaving mice, while its inhibition hinders it. Thus, activation of midbrain dopamine can operate as a teaching signal that triggers NeoHebbian LTP and promotes supervised learning., (© 2024. The Author(s).)

The excitation-inhibition imbalance manifesting as epileptic activities in Alzheimer's disease is gaining more and more attention, and several potentially involved cellular and molecular pathways are currently under investigation. Based on in vitro studies, dopamine D1-type receptors in the anterior cingulate cortex and the hippocampus have been proposed to participate in this peculiar co-morbidity in mouse models of amyloidosis. Here, we tested the implication of dopaminergic transmission in vivo in the Tg2576 mouse model of Alzheimer's disease by monitoring epileptic activities via intracranial EEG before and after treatment with dopamine antagonists. Our results show that neither the D1-like dopamine receptor antagonist SCH23390 nor the D2-like dopamine receptor antagonist haloperidol reduces the frequency of epileptic activities. While requiring further investigation, our results indicate that on a systemic level, dopamine receptors are not significantly contributing to epilepsy observed in vivo in this mouse model of Alzheimer's disease., (© 2024 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Competing Interests: Conflict of interest: M.F. reports having received grants, consulting fees, and/or honoraria and delivering lectures for Abbott, Amarin, Amgen, AstraZeneca, Ajanta, Kowa, Merck, Novartis and Co, Organon, Pfizer, Recordati, Sanofi/Regeneron, Servier, SMB, Ultragenyx, and Viatris. F.C. reports having received non-financial support and speaking fees for Amgen, MSD, Novartis, Sanofi, and Pfizer. Y.C. reports having received consultant or speaking fees for Bayer, BMS/Pfizer, Boehringer Ingelheim, Novartis, Sanofi, and Servier. M.Z. declares research grants from Amarin Corp. and lecture fees from Organon. The other authors have no declaration.

Mitochondria are integrative hubs central to cellular adaptive pathways. Such pathways are critical in highly differentiated postmitotic neurons, the plasticity of which sustains brain function. Consequently, defects in mitochondria and in their dynamics appear instrumental in neurodegenerative diseases and may also participate in cognitive impairments. To directly test this hypothesis, we analyzed cognitive performances in a mouse mitochondria-based disease model, because of haploinsufficiency in the mitochondrial optic atrophy type 1 (OPA1) protein involved in mitochondrial dynamics. In males, we evaluated adult hippocampal neurogenesis parameters using immunohistochemistry. We performed a battery of tests to assess basal behavioral characteristics and cognitive performances, and tested putative treatments. While in dominant optic atrophy (DOA) mouse models, the known main symptoms are late onset visual deficits, we discovered early impairments in hippocampus-dependent spatial memory attributable to defects in adult neurogenesis. Moreover, less connected adult-born hippocampal neurons showed a decrease in mitochondrial content. Remarkably, voluntary exercise or pharmacological treatment targeting mitochondrial dynamics restored spatial memory in DOA mice. Altogether, our study identifies a crucial role for OPA1-dependent mitochondrial functions in adult neurogenesis, and thus in hippocampal-dependent cognitive functions. More generally, our findings show that adult neurogenesis is highly sensitive to mild mitochondrial defects, generating impairments in spatial memory that can be detected at an early stage and counterbalanced by physical exercise and pharmacological targeting of mitochondrial dynamics. Thus, amplification of mitochondrial function at an early stage appears beneficial for late-onset neurodegenerative diseases., Competing Interests: The authors declare no competing financial interests., (Copyright © 2023 Andraini et al.)

Absolute measurement of light intensity is sought for in multiple areas of chemistry, biology, physics, and engineering. It can be achieved by using an actinometer from analyzing the time-course of its reaction extent on applying constant light. However, most reported actinometers exploit the absorbance observable for reporting the reaction extent, which is not very sensitive nor relevant in imaging systems. In this work, we report a series of hydrophobic and hydrophilic caged fluorophores that overcome the preceding limitations. Based on the robust pyranine backbone, they can easily be synthesized on a large scale in one to a few steps. Their brightness increases over illumination and their uncaging cross-sections have been thoroughly characterized upon one- and two-photon excitation. As a demonstration of their use, we calibrated light intensity in various chemical and biological samples, which have been observed with epifluorescence and confocal imaging systems., Competing Interests: The authors have a patent related to the content of this paper., (This journal is © The Royal Society of Chemistry.)

Mood disorders are associated with hypothalamic-pituitary-adrenal axis overactivity resulting from a decreased inhibitory feedback exerted by the hippocampus on this brain structure. Growing evidence suggests that antidepressants would regulate hippocampal excitatory/inhibitory balance to restore an effective inhibition on this stress axis. While these pharmacological compounds produce beneficial clinical effects, they also have limitations including their long delay of action. Interestingly, non-pharmacological strategies such as environmental enrichment improve therapeutic outcome in depressed patients as in animal models of depression. However, whether exposure to enriched environment also reduces the delay of action of antidepressants remains unknown. We investigated this issue using the corticosterone-induced mouse model of depression, submitted to antidepressant treatment by venlafaxine, alone or in combination with enriched housing. We found that the anxio-depressive phenotype of male mice was improved after only two weeks of venlafaxine treatment when combined with enriched housing, which is six weeks earlier than mice treated with venlafaxine but housed in standard conditions. Furthermore, venlafaxine combined with exposure to enriched environment is associated with a reduction in the number of parvalbumin-positive neurons surrounded by perineuronal nets (PNN) in the mouse hippocampus. We then showed that the presence of PNN in depressed mice prevented their behavioral recovery, while pharmacological degradation of hippocampal PNN accelerated the antidepressant action of venlafaxine. Altogether, our data support the idea that non-pharmacological strategies can shorten the onset of action of antidepressants and further identifies PV interneurons as relevant actors of this effect., (© 2023. The Author(s).)

The link between Alzheimer's disease (AD) and network hypersynchrony - manifesting as epileptic activities - received considerable attention in the past decade. However, several questions remain unanswered as to its mechanistic underpinnings. Therefore, our objectives were (1) to better characterise epileptic events in the Tg2576 mouse model throughout the sleep-wake cycle and disease progression via electrophysiological recordings and (2) to explore the involvement of noradrenergic transmission in this pathological hypersynchrony. Over and above confirming the previously described early presence and predominance of epileptic events during rapid-eye-movement (REM) sleep, we also show that these events do not worsen with age and are highly phase-locked to the section of the theta cycle during REM sleep where hippocampal pyramidal cells reach their highest firing probability. Finally, we reveal an antiepileptic mechanism of noradrenergic transmission via α1-adrenoreceptors that could explain the intriguing distribution of epileptic events over the sleep-wake cycle in this model, with potential therapeutic implications in the treatment of the epileptic events occurring in many AD patients., Competing Interests: Disclosure statement The authors have no actual or potential conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)