Marleen Verhoye

Social relationships profoundly shape the perception of communication signals. In animals that form long-term social bonds, sensory cues such as vocalizations, scent, or physical appearance, and rewarding mating experiences can become associated with a bonded mate. While this natural process has hallmarks of some forms of associative learning, little is known about where or how these experiences shape neural circuits over the course of pair bonding. We used whole-brain BOLD fMRI in female songbirds to explore experience-dependent changes in neural activity in response to male songs. Pair bonding experiences drove changes in activation in response to the partner's song within secondary auditory areas as well as two regulatory hubs that receive sensory input and connect to circuits that generate behavioral responses. In contrast, mere exposure to the vocal interactions of a neighboring pair did not result in changes in response to the neighbor's song within the same areas, suggesting that pair bonding uniquely impacts auditory responses to familiar songs in select sensory and integrative circuits. Moreover, within the areas that showed increased activation for the partner's song over the course of pair bonding, we observed diminished activation in response to the partner's song after blocking D1 dopamine receptors, indicating a potential role for dopamine in the expression or maintenance of preference for the partner's song. Eavesdropping females had changes in neural activation in response to the familiar song in a different suite of brain regions that were not affected by dopamine manipulation. Our data identify a potential circuit in which concurrent activation of sensory, reward, and regulatory hubs integrates multisensory information from social interactions and leads to the emergence of acoustic preferences and formation of long-lasting social bonds.

Cerebrovascular dysfunction, including reduced cerebral blood flow (CBF) and cerebrovascular reactivity (CVR), contributes to Alzheimer’s disease (AD). Caloric restriction (CR) and resveratrol (Rsv) benefit vascular health, yet their impact on CBF and CVR in AD remains unclear. Here, we investigated the cerebrovascular effects of 40% CR or Rsv supplementation in WT and TgF344-AD rats. Using pseudo-continuous arterial spin labelling (pCASL) MRI, we observed that male Tg control (Ctrl) rats exhibited reduced relative CBF (rCBF) and absolute CBF (aCBF) in the caudate-putamen at baseline compared to WT Ctrl and Tg Rsv rats, while Rsv restored CBF to WT levels. Male Rsv rats also showed higher rCBF than CR rats in the somatosensory cortex, irrespective of genotype. In the cingulate cortex, male Tg rats had lower rCBF than WT, irrespective of treatment. During hypercapnia, Tg males displayed lower rCBF and aCBF across multiple regions, while Rsv increased rCBF in cingulate cortex and somatosensory cortex, regardless of genotype. In females, treatments did not affect baseline or hypercapnic CBF, although CR and Rsv reduced CVR compared to Ctrl. In summary, these findings suggest Rsv reverses AD-related hypoperfusion in males, whereas CR may impair cerebrovascular responsiveness in females, highlighting the need for sex-specific therapeutic strategies.

Huntington’s disease (HD) is a progressive neurodegenerative disease affecting motor and cognitive abilities, as well as exhibiting psychiatric manifestations. Studies in people with HD (PwHD) consistently report atrophy of the caudate and putamen as an early pathological event and is therefore considered an early biomarker. Investigating whether similar phenotypic features are apparent in rodent HD models is important since it could have translational potential in evaluating the efficacy of novel therapeutic strategies. We used high-resolution anatomical images to longitudinally investigate brain morphology in the zQ175DN heterozygous mouse model (HET) and wildtype littermates (WT) at 3, 6, and 10 months of age (M), which reflect different stages of phenotypic progression. We investigated volumetric alterations using semi-automatic segmentations of HD on relevant regions-of-interest (striatum, cerebellum, corpus callosum, cerebral cortex, ventricles, and total brain volume) and whole brain voxel-wise Tensor Based Morphometry (TBM) analysis. The striatum showed the earliest progressive lower absolute volume in HET mice compared to WT, starting from 3M, followed by lower absolute volume of cortex and corpus callosum concomitantly at 6 and 10M. TBM highlighted lower relative local volume in the rostral-medial striatum at all ages, and in cerebral cortex in HET mice at 6 and 10M. A bigger relative local volume in the cerebellum was observed at all ages in HET mice, and in the globus pallidus, substantia nigra, at 6 and 10M. Overall, this study revealed key structural abnormalities that resemble the natural history of PwHD. Hence, analysis of brain structure through MRI in the zQ175DN heterozygous mouse model holds potential for testing disease-modifying treatments expected to slow down or prevent structural degeneration. Highlights: The striatum of zQ175DN heterozygous mice shows volume decrease at 3 months compared to WT mice Widespread volume reductions are observed from 6 months in zQ175DN heterozygous mice Tensor Based Morphometry highlights vulnerability of the dorsomedial striatum in the zQ175DN heterozygous mouse model

A Proliferation-Inducing Ligand (APRIL) is a tumour necrosis factor superfamily member with multiple effector roles in the peripheral and central nervous system (CNS). In the CNS, APRIL helps maintain immune homeostasis and supports neuronal survival, yet whether it can therapeutically modulate acute neuro-inflammatory and neurodegenerative processes is unclear. To investigate this in a severe neuro-inflammatory context, we tested whether local APRIL delivery can influence microglial/astrocytic responses and demyelination in the cuprizone (CPZ) mouse model of neuro-inflammation and demyelination. We applied adeno-associated virus (AAV)–mediated gene transfer to drive APRIL expression by cortical neurons positioned directly above the splenium of the corpus callosum. Following CPZ intoxication, we evaluated microglial and astrocytic activation and myelin content by in vivo T2 and diffusion magnetic resonance imaging (MRI), and validated them by post-mortem quantitative immunohistochemistry (IHC) and bulk transcriptomic and proteomic profiling. T2 and diffusion MRI, corroborated by quantitative IHC, demonstrated that secretion of APRIL by cortical neurons attenuated CPZ-induced microglial recruitment and demyelination in the splenium, but not in the cortex. Integrated transcriptome-proteome analysis of splenium and cortex, further supported by IHC, highlighted astroglial lipid-metabolic circuitry - marked by the astrocytic fatty-acid-binding protein 7 (Fabp7) - as a candidate axis underlying APRIL’s effects to reduce inflammatory cell recruitment and myelin preservation. AAV-mediated expression of APRIL by cortical neuron counteracted microglial recruitment and demyelination in the splenium of CPZ-treated mice. Our multi-omics integration analysis nominated several pathways, including Fabp7-linked astrocytic lipid metabolism, to elucidate APRIL’s mechanism of action. Together, these findings provide a framework for the mechanistic dissection of APRIL’s therapeutic potential and further translational evaluation in CNS pathologies characterised by acute neuro-inflammatory responses.

Sleep alterations are known to occur in Alzheimer’s disease (AD), before cognitive symptoms become apparent, and are thought to play an important role in the pathophysiology of AD. However, knowledge on the extent of macro- and microstructural changes of sleep during early, presymptomatic stages of AD is limited. We hypothesize that Aβ-induced perturbations of neuronal activity disrupt this oscillatory activity during sleep at pre-plaque stages of AD. In this study, we aimed to assess hippocampal oscillatory activity during sleep at pre- and early-plaque stages of AD, by performing 24-hour hippocampal electrophysiological measurements in TgF344-AD rats and wildtype littermates at pre- and early-plaque stages of AD. To provide a mechanistic understanding, histological analysis was performed to quantify GABA-ergic, glutamatergic and cholinergic synapses. We observed a differential impact of AD on hippocampal activity during rapid eye movement (REM) and non-REM (NREM) sleep, in the absence of robust changes in circadian rhythm. TgF344-AD rats demonstrated increased duration of sharp wave-ripples during NREM sleep, irrespective of age. Interestingly, a significantly decreased theta-gamma coupling was observed in TgF344-AD rats, prior to amyloid plaque deposition, which was partially restored at the early-plaque stage. The partial recovery of hippocampal activity during REM sleep coincided with an increased number of cholinergic synapses in the hippocampus during the early-plaque stage in TgF344-AD rats, suggestive of basal forebrain cholinergic compensation mechanisms. The results from this study reveal early changes in hippocampal activity prior to Aβ plaque deposition in AD. In addition, the current findings imply an important role of the cholinergic system to compensate for AD-related network alterations, thereby partially restoring sleep architecture and hippocampal activity.

Introduction: Dietary interventions such as caloric restriction (CR) exert positive effects on brain health. Unfortunately, poor compliance hinders the success of this approach. A proposed alternative is resveratrol (Rsv), a CR-mimetic known to promote brain health. Direct comparison between the effects of Rsv and CR on brain health is lacking, with limited knowledge on their sex-specific effects. Therefore, we aimed to compare and unravel the sex-specific impact of these dietary interventions on spontaneous brain activity.Methods: Here, we used resting-state fMRI to investigate functional connectivity (FC) changes in five prominent resting-state brain networks (RSNs) in healthy 4 month old male and female F344 rats supplemented to either 40% CR or daily Rsv supplementation (10 mg/kg, oral) for the duration of 1 month.Results: Our results demonstrated a decreased body weight (BW) in CR rats, as well as an increase in body weight in male Rsv supplemented rats, compared to female Rsv supplemented rats, whereas this difference between sexes was not observed in the control or CR groups. Furthermore, we found that both CR or Rsv supplementation induce a female-specific decrease of FC between the subcortical network and hippocampal network, and between the subcortical network and lateral cortical network. Moreover, Rsv supplementation lowered FC within the hippocampal network and between the hippocampal and the default mode like network, the lateral cortical network and the sensory network—an effect not observed for the CR rats.Discussion: Our findings reveal that both CR and Rsv induce a similar female-specific decrease of FC in RSNs associated with memory and emotion, all the while CR and Rsv induce dissimilar changes in body weight and other within- and between-RSN FC measures. Altogether, this study provides insight into the effects and comparability of short-term CR and Rsv supplementation on brain connectivity within- and between-RSNs in both male and female F344 rats, providing a FC reference for future research of dietary effects.

Templates for the acquisition of large datasets such as the Human Connectome Project guide the neuroimaging community to reproducible data acquisition and scientific rigor. By contrast, small animal neuroimaging often relies on laboratory-specific protocols, which limit cross-study comparisons. The establishment of broadly validated protocols may facilitate the acquisition of large datasets, which are essential for uncovering potentially small effects often seen in functional MRI (fMRI) studies. Here, we outline a procedure for the acquisition of fMRI datasets in rats and describe animal handling, MRI sequence parameters, data conversion, preprocessing, quality control and data analysis. The procedure is designed to be generalizable across laboratories, has been validated by using datasets across 20 research centers with different scanners and field strengths ranging from 4.7 to 17.2 T and can be used in studies in which it is useful to compare functional connectivity measures across an extensive range of datasets. The MRI procedure requires 1 h per rat to complete and can be carried out by users with limited expertise in rat handling, MRI and data processing.

Introduction: Dietary interventions such as caloric restriction (CR) exert positive effects on brain health. Unfortunately, poor compliance hinders the success of this approach. A proposed alternative is resveratrol (Rsv), a CR–mimetic known to promote brain health. Direct comparison between the effects of Rsv and CR on brain health is lacking, with limited knowledge on their sex-specific effects. Therefore, we aimed to compare and unravel the sex-specific impact of these dietary interventions on spontaneous brain activity. Methods: Here, we used resting-state fMRI to investigate functional connectivity (FC) changes in five prominent resting-state brain networks (RSNs) in healthy four month old male and female F344 rats supplemented to either 40% CR or daily Rsv supplementation (10 mg/kg, oral) for the duration of one month. Results: Our results demonstrated a decreased body weight (BW) in CR rats, as well as an increase in body weight in male Rsv supplemented rats, compared to female Rsv supplemented rats, whereas this difference between sexes was not observed in the control or CR groups. Furthermore, we found that both CR or Rsv supplementation induce a female-specific decrease of FC between the subcortical network and hippocampal network, and between the subcortical network and lateral cortical network. Moreover, Rsv supplementation lowered FC within the hippocampal network and between the hippocampal and the default mode like network, the lateral cortical network and the sensory network – an effect not observed for the CR rats. Finally, we observed an overall lower FC in male rats compared to females, irrespective of dietary intervention, within the subcortical network and between the subcortical, the sensory and default mode like network. Discussion: Our findings reveal that both CR and Rsv induce a similar female–specific decrease of FC in RSNs associated with memory and emotion, all the while CR and Rsv induce dissimilar changes in body weight and other within– and between RSN FC measures. Altogether, this study provides insight into the effects and comparability of short-term CR and Rsv supplementation on brain connectivity within and between RSNs in both male and female F344 rats, providing a FC reference for future research of dietary effects.