The protease caspase-3 is a key mediator of apoptotic programmed cell death. But weak or transient caspase activity can contribute to neuronal differentiation, axonal pathfinding, and synaptic long-term depression. Despite the importance of sublethal, or nonapoptotic, caspase activity in neurodevelopment and neural plasticity, there has been no simple method for mapping and quantifying nonapoptotic caspase activity (NACA) in rodent brains. We therefore generated a transgenic mouse expressing a highly sensitive and specific fluorescent reporter of caspase activity, with peak signal localized to the nucleus. As a proof of concept, we first obtained evidence that NACA influences neurophysiology in an amygdalar circuit. Then focusing on the amygdala, we were able to quantify a sex-specific persistent elevation in caspase activity in females after restraint stress. This simple in vivo caspase activity reporter will facilitate systems-level studies of apoptotic and nonapoptotic phenomena in behavioral and pathol...

To understand a dialogue, we need to know the topics that are being discussed. This enables us to integrate our knowledge of what was said previously to interpret the current dialogue. This study involved a large-scale behavioral experiment conducted online and a separate fMRI experiment, both testing human participants. In both, we selectively manipulated knowledge about the narrative content of dialogues presented in short videos. The clips were scenes from situation comedies that were split into two parts. The speech in the part 1 clips could either be presented normally or spectrally rotated to render it unintelligible. The part 2 clips that concluded the scenes were always presented normally. The behavioral experiment showed that knowledge of the preceding narrative boosted memory for the part 2 clips as well as increased the intersubject semantic similarity of recalled descriptions of the dialogues. The fMRI experiment replicated the finding that prior knowledge improved memory for the conclusions of...

Given its inputs from auditory structures and neuromodulatory systems, the posterior tail of the striatum is ideally positioned to influence behavioral responses to acoustic stimuli according to context and previous rewards. Results from previous studies indicate that neurons in this striatal region display selective responses to sounds. However, it is not clear whether different striatal cell classes code for distinct features of sounds or how different striatal output pathways may use acoustic information to guide behavior. Here we compared the sound-evoked responses of posterior striatal neurons that form the striatal direct pathway (and express the dopamine receptor D1) to the responses of neighboring neurons in naive mice. We achieved this via optogenetic photo-identification of D1-expressing neurons during extracellular electrophysiological recordings in awake head-fixed mice of both sexes. We found that the frequency tuning of sound-responsive direct-pathway striatal neurons is comparable with that ...

Functional magnetic resonance imaging (fMRI) combined with population receptive field (pRF) mapping allows for associating positions on the visual cortex to areas on the visual field. Apart from applications in healthy subjects, this method can also be used to examine dysfunctions in patients suffering from partial visual field losses. While such objective measurement of visual deficits (scotoma) is of great importance for, e.g., longitudinal studies addressing treatment effects, it requires a thorough assessment of accuracy and reproducibility of the results obtained. In this study, we quantified the reproducibility of pRF mapping results within and across sessions in case of central visual field loss in a group of 15 human subjects. We simulated scotoma by masking a central area of 2° radius from stimulation to establish ground-truth conditions. This study was performed on a 7T ultra-high field MRI scanner for increased sensitivity. We found excellent intrasession and intersession reproducibility for the...

Limited reproducibility and validity are major sources of concern in biology and other fields of science. Their origins have been extensively described and include material variability, incomplete materials and methods report, results selection, defective experimental design, lack of power, inappropriate statistics, overinterpretation, and reluctance to publish negative results. Promoting complete and accurate communication of positive and negative results is a major objective. Multiple steps in this direction are taken, but they are not sufficient and the general construction of articles has not been questioned. I propose here a simple change with a potentially strong positive impact. First, when they complete a substantial coherent set of experiments, scientists deposit their positive or negative results in a database [“deposited results,” (DRs)], including detailed materials, methods, raw data, analysis, and processed results. The DRs are technically reviewed and validated as “validated DRs” (vDRs) or r...

This study assesses the involvement in human motor learning, of the ventrolateral prefrontal cortex (BA 9/46v), a somatic region in the middle frontal gyrus. The potential involvement of this cortical area in motor learning is suggested by studies in nonhuman primates which have found anatomic connections between this area and sensorimotor regions in frontal and parietal cortex, and also with basal ganglia output zones. It is likewise suggested by electrophysiological studies which have shown that activity in this region is implicated in somatic sensory memory and is also influenced by reward. We directly tested the hypothesis that area 9/46v is involved in reinforcement-based motor learning in humans. Participants performed reaching movements to a hidden target and received positive feedback when successful. Before the learning task, we applied continuous theta burst stimulation (cTBS) to disrupt activity in 9/46v in the left or right hemisphere. A control group received sham cTBS. The data showed that cT...

A strong bidirectional link between metabolic and psychiatric disorders exists; yet the molecular basis underlying this interaction remains unresolved. Here we explored the role of the brown fat issue (BAT) as modulatory interface, focusing on the involvement of uncoupling protein 1 (UCP-1), a key metabolic regulator highly expressed in BAT, in the control of emotional behavior. Male and female constitutive UCP-1 knockout (KO) mice were used to investigate the consequences of UCP-1 deficiency on anxiety-related and depression-related behaviors under mild thermogenic (23°C) and thermoneutral (29°C) conditions. UCP-1 KO mice displayed a selective enhancement of anxiety-related behavior exclusively under thermogenic conditions, but not at thermoneutrality. Neural and endocrine stress mediators were not affected in UCP-1 KO mice, which showed an activation of the integrated stress response alongside enhanced Fibroblast-growth factor-21 (FGF-21) levels. However, viral-mediated overexpression of FGF-21 did not...

The CA1 pyramidal neurons are embedded in an intricate local circuitry that contains a variety of interneurons. The roles these interneurons play in the regulation of the excitatory synaptic plasticity remains largely understudied. Recent experiments showed that recurring cholinergic activation of α7 nACh receptors expressed in oriens-lacunosum-moleculare (OLMα2) interneurons can directly induce LTP in Schaffer collateral (SC)–CA1 synapses. Here, we pair in vitro studies with biophysically based modeling to uncover the underlying mechanisms. According to our model, α7 nAChR activation increases OLM GABAergic activity. This results in the inhibition of the fast-spiking interneurons that provide feedforward inhibition onto CA1 pyramidal neurons. This disinhibition, paired with tightly timed SC stimulation, can induce potentiation at the excitatory synapses of CA1 pyramidal neurons. Our work details the role of cholinergic modulation in disinhibition-induced hippocampal plasticity. It relates the timing of ch...

Fragile X syndrome (FXS) is a leading monogenic cause of intellectual disability and autism spectrum disorders, spurring decades of intense research and a multitude of mouse models. So far, these models do not recapitulate the genetic underpinning of classical FXS—CGG repeat-induced methylation of the Fmr1 locus—and their findings have failed to translate into the clinic. We sought to answer whether this disparity was because of low repeat length and generated a novel mouse line with 341 repeats, Fmr1hs341 , which is the largest allele in mice reported to date. This repeat length is significantly longer than the 200 repeats generally required for methylation of the repeat tract and promoter region in FXS patients, which leads to silencing of the FMR1 gene. Bisulfite sequencing fails to detect the robust methylation expected of FXS in Fmr1hs341 mice. Quantitative real-time PCR and Western blotting results also do not resemble FXS and instead produce a biochemical profile consistent with the fragile X-associ...

Neural oscillations are thought to reflect low-level operations that can be used for higher-level cognitive functions. Here, we investigated the role of brain rhythms in the 1–30 Hz range by recording MEG in human participants performing a visual delayed match-to-sample paradigm in which orientation or spatial frequency of sample and probe gratings had to be matched. A cue occurring before or after sample presentation indicated the to-be-matched feature. We demonstrate that alpha/beta power decrease tracks the presentation of the informative cue and indexes faster responses. Moreover, these faster responses coincided with an augmented phase alignment of slow oscillations, as well as phase–amplitude coupling between slow and fast oscillations. Importantly, stimulus decodability was boosted by both low alpha power and high beta power. In summary, we provide support for a comprehensive framework in which different rhythms play specific roles: slow rhythms control input sampling, while alpha (and beta) gates t...