Biology subjects

Henckens, M. J. A. G.

Publications and source records attributed to Henckens, M. J. A. G..

5 recordsLinked to original sources

bioRxiv2026

Sex differences in fear extinction are conditional, not categorical

Threat memories are dynamic, and their behavioral expression can change with subsequent experience and the passage of time. Extinction training can reduce conditioned fear responses, yet these responses may re-emerge over time through spontaneous recovery. Although biological sex has been implicated as modulatory factor in fear and extinction memory processes, studies have reported inconsistent findings. Here, we investigated how differences in extinction training and the timing of memory assessment influence extinction memory in male and female mice. Using contextual fear conditioning, we assessed fear acquisition and threat retention, characterized within-session and across-session extinction during repeated training, and compared shorter (3-minute) and longer (6-minute) daily extinction sessions. We subsequently evaluated extinction memory retention and spontaneous recovery at a later time point. Estrous-cycle stage in females was monitored daily throughout the experimental protocol to examine its potential association with fear and extinction behavior. We found that males and females demonstrated comparable fear acquisition and threat memory, as well as similar extinction progression across days. During longer extinction sessions, but not shorter, males showed greater within-session reductions in freezing, whereas females exhibited modestly higher overall freezing. We found no significant sex difference in the magnitude of spontaneous recovery. There was no significant association between estrous-cycle stage and freezing behavior. Together, our findings suggest that sex-dependent differences in contextual fear extinction are not uniformly expressed, but rather depend on the experimental conditions under which extinction is assessed

neuroscience↗

bioRxiv2024

The Neural Blueprint of Stress Susceptibility: Brain-wide neuronal activity associated with the consequences of stress

Understanding the neurobiological mechanisms of stress susceptibility is key to advancing our insight into stress-related psychopathology like post-traumatic stress disorder (PTSD). Preclinical animal models however typically lack translationally relevant brain readouts. Here, we used a mouse model for severe stress, segregating mice into stress-susceptible and resilient groups. We analyzed and contrasted their whole-brain neuronal activity pre-, peri- and post-stress exposure and compared functional connectivity of the salience (SN), default mode (DMN) and executive control network (lateral cortical network (LCN) in rodents). We found that stress-susceptible mice exhibited pre-existing hyperactivity in the lateral orbital area, a potential risk factor for stress vulnerability, and heightened retrosplenial cortex activity peri- and post-stress, potentially contributing to maladaptive fear memory. Upon stress exposure, susceptible mice showed strong recruitment of visual and memory-related areas, whereas resilient mice displayed marked reductions in retrosplenial activity and increased activation in the agranular insula and ventral striatum. Observations of enhanced intra-SN and SN-DMN connectivity in susceptible mice mirrored those observed in individuals with PTSD. Moreover, susceptible mice displayed aberrant DMN-LCN network pre- and peri-stress. These findings highlight the importance of dynamic network interactions in stress susceptibility and suggest novel brain region targets for (early) intervention.

neuroscience↗

bioRxiv2024

Unravelling the neurocognitive mechanisms underlying counterconditioning in humans

Counterconditioning (CC) aims to enhance extinction of threat memories by establishing new associations of opposite valence. While its underlying neurocognitive mechanisms remain largely unexplored, previous studies suggest qualitatively different mechanisms from regular extinction. In this functional MRI study, participants underwent categorical threat conditioning (CS+/CS-: images of animals/tools), followed by either CC (CS+ images reinforced with monetary rewards, n=24) or regular extinction (n=24). The following day, we assessed spontaneous recovery of threat responses and episodic memory for CS+ and CS-category exemplars. While the ventromedial prefrontal cortex (vmPFC) was activated during regular extinction, participants undergoing CC showed persistent CS+-specific deactivation of the vmPFC and hippocampus, and CS+-specific activation of the nucleus accumbens (NAcc). The following day, physiological threat responses returned in the regular extinction group, but not in the CC group. Counterconditioning furthermore strengthened episodic memory for CS+ exemplars presented during CC, and retroactively also for CS+ exemplars presented during the threat conditioning phase. Our findings confirm that CC leads to more persistent extinction of threat memories, as well as altered consolidation of the threat conditioning episode. Crucially, we show a qualitatively different activation pattern during CC versus regular extinction, with a shift away from the vmPFC and towards the NAcc.

neuroscience↗

bioRxiv2024

Hippocampal trauma memory processing conveying susceptibility to traumatic stress

While the majority of the population is ever exposed to a traumatic event during their lifetime, only a fraction develops posttraumatic stress disorder (PTSD). Disrupted trauma memory processing has been proposed as a core factor underlying PTSD symptomatology. We used transgenic Targeted- Recombination-in-Active-Populations (TRAP) mice to investigate potential alterations in trauma- related hippocampal memory engrams associated with the development of PTSD-like symptomatology. Mice were exposed to a stress-enhanced fear learning paradigm, in which prior exposure to a stressor affects the learning of a subsequent fearful event (contextual fear conditioning using foot shocks), during which neuronal activity was labeled. One week later, mice were behaviorally phenotyped to identify mice resilient and susceptible to developing PTSD-like symptomatology. Three weeks post-learning, mice were re-exposed to the conditioning context to induce remote fear memory recall, and associated hippocampal neuronal activity was assessed. While no differences in the size of the hippocampal neuronal ensemble activated during fear learning were observed between groups, susceptible mice displayed a smaller ensemble activated upon remote fear memory recall in the ventral CA1, higher regional hippocampal PV+ neuronal density and a relatively lower activity of PV+ interneurons upon recall. Investigation of potential epigenetic regulators of the engram revealed rather generic (rather than engram-specific) differences between groups, with susceptible mice displaying lower hippocampal histone deacetylase 2 expression, and higher methylation and hydroxymethylation levels. These finding implicate variation in epigenetic regulation within the hippocampus, as well as reduced regional hippocampal activity during remote fear memory recall in interindividual differences in susceptibility to traumatic stress.

neuroscience↗

bioRxiv2020

Aberrant ventral dentate gyrus structure and function in individuals susceptible to post-traumatic stress disorder

Post-traumatic stress disorder (PTSD) is a psychiatric disorder vulnerable individuals can develop following a traumatic event, whereas others are resilient. Enhanced insight into the mechanistic underpinnings contributing to these inter-individual differences in PTSD susceptibility is key to improved treatment and prevention. Aberrant function of the hippocampal dentate gyrus (DG) may contribute to its psychopathology, with the dorsal DG potentially encoding trauma memory generalization and the ventral DG anxiety. Using a mouse model, we investigated the association between deviant DG structure and function and susceptibility to develop PTSD-like symptoms following trauma. Mice were exposed to a traumatic event (unpredictable, inescapable foot shocks) and tested for PTSD symptomatology following recovery. In three independent experiments, DG neuronal morphology, synaptic protein gene expression and neuronal activity during trauma encoding and recall were assessed. Behaviorally, PTSD-like animals displayed some increased anxiety-like behavior already prior to trauma, increased novelty-induced freezing, but no clear differences in remote trauma memory recall. Comparison of the ventral DG of PTSD-like vs resilient mice revealed lower spine density, reduced expression of the postsynaptic protein homer 1b/c gene, a larger population of neurons active during trauma encoding and a greater presence of somatostatin neurons to be associated with PTSD susceptibility. In contrast, the dorsal DG of PTSD-like animals did not differ in terms of spine density or gene expression, but displayed more active neurons during trauma encoding and a lower amount of somatostatin neurons. These data propose a critical role for -mainly the ventral-DG in establishing symptomatology addressed in this PTSD model.

neuroscience↗