Biology subjects

Homberg, J. R.

Publications and source records attributed to Homberg, J. R..

16 recordsLinked to original sources

bioRxiv2026

Resting state fMRI detects pathological functional brain connectivity in the Ndufs4 knockout mouse model of Leigh syndrome during the pre-symptomatic stage of the disease

Leigh syndrome (LS) is a progressive encephalopathy and generally regarded as the most common inborn mitochondrial disease. Mutations in mitochondrial respiratory complex I are common in patients with LS and a mutational hotspot has been identified in the gene that encodes the NDUFS4 subunit of respiratory complex I. The Ndufs4 knockout mouse (Ndufs4 KO) model of LS closely resembles the phenotypes of LS patients and show like the patient brain lesions when the symptoms are manifested. It is speculated but unproven that brain functional connectivity may precede the onset of symptoms. Therefore, the present study was set out to investigate the progression of brain functional connectives in Ndufs4 KO mice before and after the manifestation of LS-like symptoms using in vivo resting-state functional magnetic resonance imaging (rs-fMRI). Since the brain lesions may be caused by increased reactive oxygen species (ROS) in the brain, we also examined the potential protective effect of KH176, a small molecular for modulating ROS levels, on brain functional connectivity. Rs-fMRI results showed that in Ndufs4 KO mice the functional connectivity of the piriform cortex, motor cortex, barrel cortex, visual cortex, auditory cortex, prefrontal cortex, lateral striatum, ventral striatum cortex and amygdala was increased, starting from the pre-symptomatic stage (middle stage) to the symptomatic stage (late stage) of the disease. KH176 had no effect on the changes in functional connectivity in the mice. In conclusion, these results show that there are abnormalities in functional connectivity in Ndufs4 KO mice during the pre-symptomatic phase of the disease and that KH176 treatment does not modify the connectivity changes.

neuroscience↗

bioRxiv2025

Increased cocaine self-administration and prefrontal cortical dysregulation of glutamatergic and GABAergic signaling in a rat model for sensory processing sensitivity

While all organisms are tuned to the environment, some are more sensitive than others. In humans, this is reflected by the trait sensory processing sensitivity (SPS), comprising 20-30% of the population, which is characterized by heightened emotional reactivity, deeper information processing, greater awareness of their environment, and susceptibility to overstimulation. It is expected but unproven that high SPS increases the risk for psychostimulant use. To clarify this, we selected Wistar rats on behavioral extremes related to SPS and subjected them to isolation, neutral, and enriched housing conditions, followed by cocaine self-administration (S/A). Subsequently, we investigated neurobiological differences in excitatory/inhibitory neurotransmission of the low- and high SPS-like rats by evaluating key glutamatergic and GABAergic proteins in the infralimbic (ILc) and prelimbic (PLc) subregions of the prefrontal cortex. High SPS-like rats displayed higher cocaine intake during 1h S/A training sessions in isolated versus social conditions, whereas low SPS-like rats showed similar intake across housing conditions. During 6h S/A sessions, high SPS-like rats displayed a higher cocaine intake regardless of housing and greater motivation for cocaine under a progressive ratio scheme. High SPS-like cocaine-naive rats exhibited lower expression of glutamatergic and GABAergic markers in ILc and PLc compared to low SPS-like cocaine-naive rats. The opposite occurred after cocaine exposure: low and high SPS-like rats showed lower and higher expression levels, respectively, compared to naive counterparts. In conclusion, these findings suggest that a high SPS-like trait with associated glutamatergic and GABAergic alterations might be a risk factor for the development of cocaine use disorder.

neuroscience↗

bioRxiv2025

Increased ambient temperature mitigates pathology in the Ndufs4-/- mouse model of Leigh Syndrome

Leigh syndrome (LS) is a devastating mitochondrial disease (MD) for which there is no treatment. Together with Leigh-like syndrome (LLS), LS constitutes part of the Leigh syndrome spectrum (LSS) disorders, which are the most frequent manifestation of a primary mitochondrial disease (MD) in children. Ndufs4-/- mice are a widely used animal model to study LS pathophysiology and interventions. These mice display an isolated mitochondrial complex I deficiency and a brain-specific pathomechanism. Similar to other mouse models of human disease, Ndufs4-/- mice are routinely housed and studied at a sub-thermoneutral ambient temperature. This means that these mice experience chronic cold-stress, which potentially aggravates disease symptoms and reduces their translational value. Here, we provide evidence that housing Ndufs4-/- mice at 26 {degrees}C instead of 20 {degrees}C increases their skin, core and brain temperature. At this higher temperature, Ndufs4-/- mice displayed lower energy expenditure and, importantly, a longer lifespan, pathology reversal in specific brain regions, as well as increased voluntary locomotor activity. We conclude that ambient temperature is a previously overlooked but highly relevant disease modifier in Ndufs4-/- mice. Given the reduced mitochondrial energy production and aberrant thermoregulation in LSS and other MD patients, our findings suggest that reducing energy requirements might be of therapeutic value and/or contribute to an improved quality of life in these patients. In a broader sense, our results advocate the use of (more) thermoneutral housing to evaluate pathomechanisms and intervention strategies in murine models of human disease. SignificanceWe conclude that ambient temperature is a previously overlooked but highly relevant disease modifier in Ndufs4-/- mice. Given the reduced mitochondrial energy production and aberrant thermoregulation in LS and other MD patients, our findings suggest that reducing energy requirements might be of therapeutic value and/or contribute to an improved quality of life in these patients. In a broader sense, our results clearly demonstrate why it is essential to use a (more) thermoneutral housing to evaluate pathomechanisms and intervention strategies in translational research with murine models of human disease.

neuroscience↗

bioRxiv2025

Perfect imperfections: seeking molecular and cellular asymmetries in the mouse brain

Although perfect symmetry is a mathematical ideal, many Bilateria exhibit left-right asymmetries of body, brain and behavior that are adaptive 1-3. In the human brain, various aspects of cognition are lateralized, including language 4 and handedness 5, which rely on left hemisphere dominance in most people. Brain hemispheric specialization can support parallel processing, neural efficiency, and action selection 3,6, while atypical structural or functional asymmetries are often found in neuropsychiatric disorders 7-10. Mice may be useful models for studying brain asymmetry because they show hemispheric differences of structure 11,12 and neurophysiology 13, but the extent to which molecular and cellular differences are involved remains unknown. We applied spatial transcriptomics with single molecule resolution to coronal sections from 31 adult mouse brains, to assess left-right differences of gene expression and cell types. Sections were chosen to capture the hippocampus and auditory cortex, as these two regions have shown the most prior evidence for functional asymmetry 13-15. In the hippocampus, Crhr1 (Corticotropin-Releasing Hormone Receptor 1) was more highly expressed in the pyramidal layers of CA1, CA3 and the dentate gyrus of the left hemisphere compared to the right. In the auditory cortex, three principal components capturing transcriptomic variation showed hemispheric differences, including prominent contributions from genes that have shown associations with human brain asymmetry. Overall cellular density and cell type proportions generally showed no significant hemispheric differences, with Car3 cortical excitatory neurons showing the most laterality. The transcriptional left-right differences that we found may relate to functional asymmetries for learning, memory and hearing. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=195 SRC="FIGDIR/small/675542v1_ufig1.gif" ALT="Figure 1"> View larger version (119K): org.highwire.dtl.DTLVardef@1530502org.highwire.dtl.DTLVardef@16dd244org.highwire.dtl.DTLVardef@107950corg.highwire.dtl.DTLVardef@ca52a3_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIMolecular and cellular basis of functional brain asymmetry is barely known C_LIO_LISpatial transcriptomics with cellular resolution applied to mouse brain coronal sections C_LIO_LIGenes implicated in human brain asymmetry showed hemispheric differences in mice C_LIO_LINo hemispheric differences of cell type abundances C_LI

neuroscience↗

bioRxiv2025

Different Sensitivity to Ethanol and Sucrose in DAT and SERT Knockout Rats

BackgroundDopamine and serotonin are key regulators of reward sensitivity, yet their distinct roles in motivating natural (e.g., sucrose) versus drug (e.g., ethanol) rewards remain unclear. Understanding these mechanisms could help explain individual variability in reward processing relevant to substance use vulnerability. MethodsWe assessed reward sensitivity in dopamine transporter (DAT) and serotonin transporter (SERT) knockout (KO) rats using both home cage (two-bottle choice for sucrose and ethanol) and operant paradigms (Pavlovian and instrumental learning). ResultsDAT KO rats showed lower sucrose preference (-27% for 2%, -13% for 4%) and intake (-42% for 4%), diminished Pavlovian responding for sucrose (-68%), and slower acquisition of sucrose-taking behavior ([~]+30 days) compared to WT rats. DAT KO rats also showed reduced ethanol preference in the home cage (-16%) despite an unchanged intake. Furthermore, operant performed was markedly reduced operant performance after the sucrose-to-ethanol transition (-83%), with no increase in ethanol-taking following sucrose exposure (0% change), unlike WT controls (+41%). SERT KO rats presented reduced sucrose preference (-5%) and intake (-46%) for the 4% solution only. In addition, SERT KO rats also showed reduced Pavlovian sucrose responding (- 28%) and slower acquisition of sucrose-taking ([~]+30 days) but intact responding and learning for ethanol. In the home cage, they displayed lower ethanol preference (-35%) without significant change in operant ethanol performance. A modest overall increase in ethanol-taking was seen post-sucrose in both SERT KO and WT, but without genotype-specific effects. Conclusion and ImplicationsDAT deletion broadly impaired sensitivity for both natural sucrose and ethanol rewards, particularly under effortful or devalued conditions. In contrast, SERT deletion produced more selective impairments by disrupting sucrose operant responding and moderately reducing ethanol reward preference. These findings reveal distinct but overlapping roles of DAT and SERT in regulating reward sensitivity, with implications for understanding individual vulnerability to substance use.

animal behavior and cognition↗

bioRxiv2024

Activation mapping in multi-center rat sensory-evoked functional MRI datasets using a unified pipeline.

Functional Magnetic Resonance Imaging (fMRI) in rodents is pivotal for understanding the mechanisms underlying Blood Oxygen Level-Dependent (BOLD) signals and phenotyping animal models of disorders, amongst other applications. Despite its growing use, comparing rodent fMRI results across different research sites remains challenging due to variations in experimental protocols. Here, we aggregated and analyzed 22 sensory-evoked rat fMRI datasets from 12 imaging centers, totaling scans from 220 rats, to assess the consistency of results across diverse protocols. We applied a standardized preprocessing pipeline and evaluated the impact of different hemodynamic response function models on group and individual level activity patterns. Our analysis revealed inter-dataset variability attributed to differences in experimental design, anesthesia protocols, and imaging parameters. We identified robust activation clusters in all (22/22) datasets. The comparison between stock human models implemented in software and rat-specific models showed significant variations in the resulting statistical maps. Our findings emphasize the necessity for standardized protocols and collaborative efforts to improve the reproducibility and reliability of rodent fMRI studies. We provide open access to all datasets and analysis code to foster transparency and further research in the field.

neuroscience↗

bioRxiv2024

Sensory processing sensitivity is associated with neural synchrony and functional connectivity during threatening movies

Sensory processing sensitivity (SPS) is an evolutionarily conserved trait describing a persons sensitivity to subtle stimuli, their depth of processing, emotional reactivity, and susceptibility to being overwhelmed. SPS is considered a fundamental and evolutionarily conserved trait, yet its neural mechanisms remain insufficiently understood. Therefore, we investigated whether SPS relates to processing movies differently in the central executive (CEN), default mode (DMN), and salience (SN) networks. We obtained positive and negative dimension Sensory Processing Sensitivity Questionnaire (short-form) scores and (neutral and threat aural framing) movie-fMRI data from a population-based sample (Healthy Brain Study, N=238, agemean=34years). We performed a priori inter-subject representation similarity, activation, and inter-subject functional connectivity analyses to characterize SPS-dimension-related neural responses during movie-viewing. More similar negative dimension SPS score related to more neural synchrony in the CEN and SN during threat. Higher negative dimension SPS score related to reduced CEN-DMN functional connectivity during threat, an effect shared across between-network regions but most strongly driven by reduced connectivity between right dorsomedial prefrontal cortex and left lateral prefrontal cortex. Our findings suggest that highly sensitive individuals exhibit distinct CEN differences shaping environmental perception, process threat differently, and each SPSQ-SF dimension may involve unique neurological mechanisms.

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↗

bioRxiv2023

The universe is asymmetric, the mouse brain too.

Hemispheric brain asymmetry is a basic organizational principle of the human brain and has been implicated in various psychiatric conditions, including autism spectrum disorder. Brain asymmetry is not a uniquely human feature and is observed in other species such as the mouse. Yet, asymmetry patterns are generally nuanced, and substantial sample sizes are required to detect these patterns. In this pre-registered study, we use a mouse dataset from the Province of Ontario Neurodevelopmental Network, which comprises structural MRI data from over 2000 mice, including genetic models for autism spectrum disorder, to reveal the scope and magnitude of hemispheric asymmetry in the mouse. Our findings demonstrate the presence of robust hemispheric asymmetry in the mouse brain, such as larger right hemispheric volumes towards the anterior pole and larger left hemispheric volumes toward the posterior pole, opposite to what has been shown in humans. This suggests the existence of species-specific traits. Further clustering analysis identified distinct asymmetry patterns in autism spectrum disorder models, a phenomenon that is also seen in atypically developing participants. Our study shows potential for the use of mouse models in studying the biological bases of typical and atypical brain asymmetry but also warrants caution as asymmetry patterns seem to differ between humans and mice.

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↗

bioRxiv2020

BDNF Overexpression in the Prelimbic Cortex Does Not Reduce Anxiety- and Depression-like Behavior in Serotonin Knockout Rats

Depressive disorders are one of the leading causes of non-fatal health loss in the last decade. Adding to the burden, the available treatments not always properly work for some individuals. There is, therefore, a constant effort from clinical and preclinical studies to bring forward a better understanding of the disease and look for novel alternative therapies. Two target systems very well explored are the serotonin and the brain-derived neurotrophic factor (BDNF) systems. Selective serotonin reuptake inhibitors (SSRIs), a commonly used class of antidepressants, target the serotonin transporter (SERT) and increase serotonin levels, which in turn also leads to an increase in BDNF. A rat model lacking SERT (SERT knockout) has been a useful tool to study the interplay between serotonin and BDNF. SERT-/- rats present increased extracellular levels of serotonin, yet BDNF levels are decreased, especially in the prefrontal cortex (PFC) and hippocampus. The animals further display anxiety- and depression-like behavior. Therefore, BDNF might mediate the phenotype expressed by the SERT-/- rats. In this study, we sought to investigate whether overexpression of BDNF in the brain of SERT-/- rats would rescue its anxious and depressive-like behavior. Through stereotaxic surgery, SERT-/- and wild-type (WT) rats received BDNF or GFP lentivirus microinfusions into the prelimbic cortex subregion of the mPFC and were submitted to the sucrose consumption, open field test, and forced swim tests. Additionally, we measured hypothalamus-pituitary-adrenal (HPA)-axis reactivity. The results revealed that SERT-/- rats presented decreased sucrose intake, decreased locomotor activity, and increased escape-oriented behavior in the forced swim test compared to WT rats. BDNF upregulation in WT rats caused alterations in the HPA-axis function, resulting in elevated basal plasma corticosterone levels and decreased plasma corticosterone upon stress. In conclusion, BDNF overexpression in the PrL, in general, did not rescue SERT-/- rats from its depression- and anxiety-like behavior, and in WT animals, it caused a malfunction in the HPA-axis.

animal behavior and cognition↗

bioRxiv2020

BDNF overexpression in the ventral hippocampus promotes antidepressant- and anxiolytic-like activity in serotonin transporter knockout rats

Brain-derived neurotrophic factor is one of the most studied proteins playing a pivotal role in neuroplasticity events and vulnerability and resilience to stress-related disorders. Most importantly, BDNF is decreased in depressive patients, and increased after antidepressant treatment. Additionally, BDNF was found to be reduced in a genetic subset of depression susceptible patients carrying the human polymorphism in the serotonin transporter promoter region (5-HTTLPR). The serotonin knockout rat (SERT-/-) is one of the animal models used to investigate the underlying molecular mechanisms behind the genetic susceptibility to depression in humans. SERT-/- rats present decreased BDNF levels, especially BDNF exon IV, in the prefrontal cortex (PFC) and ventral hippocampus (vHIP), and display anxiety- and depression-like behavior. To investigate whether upregulating BDNF in the vHIP would meliorate the phenotype of SERT-/- rats, we overexpressed BDNF locally into the rat brain by means of stereotaxic surgery and submitted the animals to behavioral challenges, including the sucrose consumption, the open field, and forced swim tests. Additionally, we measured hypothalamus-pituitary-adrenal (HPA)-axis reactivity. The results showed that lentivirus-induced BDNF IV overexpression in the vHIP of SERT-/- rats promoted higher sucrose preference and sucrose intake, on the first day of the sucrose consumption test, indicative for decreased anhedonia-like behavior. Moreover, it decreased immobility time in the forced swim test, suggesting adaptive passive coping. Additionally, BDNF upregulation increased the time spent in the center of a novel environment, implying decreased novel-induced anxiety-like behavior. Finally, it promoted a stronger decrease in plasma corticosterone levels 60 minutes after restraint stress. In conclusion, modulation of BDNF IV levels in the vHIP of SERT-/- rats led to a positive behavioral outcome placing BDNF upregulation in the vHIP as a potential candidate for the development new therapeutic approaches targeting the improvement of depressive symptoms.

animal behavior and cognition↗

bioRxiv2020

Crossing the Blood-Brain-Barrier: A bifunctional liposome for BDNF gene delivery - A Pilot Study

To achieve their therapeutic effect on the brain, molecules need to pass the blood-brain-barrier (BBB). Many pharmacological treatments of neuropathologies encounter the BBB as a barrier, hindering their effective use. Pharmaceutical nanotechnology based on optimal physicochemical features and taking advantage of naturally occurring permeability mechanisms, nanocarriers such as liposomes offer an attractive alternative to allow drug delivery across the BBB. Liposomes are spherical bilayer lipid-based nanocapsules that can load hydrophilic molecules in their inner compartment and on their outer surface can be functionally modified by peptides, antibodies and polyethyleneglycol (PEG). When composed of cationic lipids, liposomes can serve as gene delivery devices, encapsulating and protecting genetic material from degradation and promoting nonviral cell transfection. In this study, we aimed to develop a liposomal formulation to encapsulate a plasmid harbouring brain-derived neurotrophic factor (BDNF) and infuse these liposomes via the peripheral bloodstream into the brain. To this end, liposomes were tagged with PEG, transferrin, and arginine and characterized regarding their physical properties, such as particle size, zeta-potential and polydispersity index (PDI). Moreover, we selected liposomes preparations for plasmid DNA (pDNA) encapsulation and checked for loading efficiency, in vitro cell uptake, and transfection. The preliminary results from this pilot study revealed that we were able to replicate the liposomes synthesis described in literature, achieving compatible size, charge, PDI, and loading efficiency. However, we could not properly determine whether the conjugation of the surface ligands transferrin and arginine to PEG worked and whether they were attached to the surface of the liposomes. Additionally, we were not able to see transfection in SH-SY5Y cells after 24 or 48 hours of incubation with the pDNA loaded liposomes. In conclusion, we synthesized liposomes encapsulation pBDNF, however, further research will be necessary to address the complete physicochemical characterization of the liposomes. Furthermore, preclinical studies will be helpful to verify transfection efficiency, cytotoxicity, and in the future, safe delivery of BDNF through the BBB.

pharmacology and toxicology↗

bioRxiv2019

Perinatal selective serotonin reuptake inhibitor exposure and behavioral outcomes: a systematic review and meta-analyses of animal studies

In the Western world, 2-5% of pregnant women use selective serotonin reuptake inhibitor (SSRI) antidepressants. There is no consensus on the potential long-term neurodevelopmental outcomes of early SSRI exposure. Our aim was to determine whether there is an overall effect of perinatal SSRI exposure in animals on a spectrum of behavioral domains. After a comprehensive database search in PubMed, PsycINFO, and Web of Science, we included 99 publications. We performed nine meta-analyses and two qualitative syntheses corresponding to different behavioral categories, aggregating data from thousands of animals. We found evidence for reduced activity and exploration behavior (standardized mean difference (SMD) -0.28 [-0.38, -0.18]), more passive stress coping (SMD -0.37 [-0.52, -0.23]), and less efficient sensory processing (SMD -0.37 [-0.69, -0.06]) in SSRI-versus vehicle-exposed animals. No differences were found for anxiety (p=0.06), social behavior, learning and memory, ingestive- and reward behavior, motoric behavior, or reflex and pain sensitivity. Exposure in the period equivalent to the human third trimester was associated with the strongest effects. HighlightsO_LIPerinatal SSRI exposure in rodents alters outcomes in three behavioral domains. C_LIO_LIIt leads to reduced activity, passive stress coping, and weaker sensory processing. C_LIO_LIFemales are understudied but seem to be less vulnerable than males. C_LIO_LIEarly postnatal exposure in rodents leads to the largest effects on behavior. C_LIO_LIThis is equivalent to the third trimester of pregnancy in humans. C_LI

animal behavior and cognition↗

bioRxiv2019

Serotonergic development of active sensing

Active sensing requires adaptive motor (positional) control of sensory organs based on contextual, sensory and task requirements, and develops postnatally after the maturation of intracortical circuits. Alterations in sensorimotor network connectivity during this period are likely to impact sensorimotor computation also in adulthood. Serotonin is among the cardinal developmental regulators of network formation, thus changing the serotonergic drive might have consequences for the emergence and maturation of sensorimotor control. Here we tested this hypothesis on an object localization task by quantifying the motor control dynamics of whiskers during tactile navigation. The results showed that sustained alterations in serotonergic signaling in serotonin transporter knockout rats, or the transient pharmacological inactivation of the transporter during early postnatal development, impairs the emergence of adaptive motor control of whisker position based on recent sensory information. A direct outcome of this altered motor control is that the mechanical force transmitted to whisker follicles upon contact is reduced, suggesting that increased excitability observed upon altered serotonergic signaling is not due to increased synaptic drive originating from the periphery upon whisker contact. These results argue that postnatal development of adaptive motor control requires intact serotonergic signaling and that even its transient dysregulation during early postnatal development causes lasting sensorimotor impairments in adulthood.

neuroscience↗

bioRxiv2019

Action of cocaine involves depletion of dopaminergic and serotonergic storage vesicles

Cocaine is known to increase the extracellular levels of dopamine (DA) and serotonin (5-HT) by inhibiting the neuronal reuptake of these monoamines. However, individuals with reduced monoamine reuptake transporter expression do not display a reduction in cocaine intake, suggesting that a mechanism other than inhibition of monoamine reuptake contributes to the rewarding and addictive effects of the psychostimulant. Here we report that cocaine depletes the dopaminergic and serotonergic storage vesicles of the rat nucleus accumbens. This cocaine-induced vesicle depletion gave rise to acute increases in the extracellular levels of DA and 5-HT, which in turn correlated with monoamine-type-specific changes in behavior. Both the neurochemical and behavioral responses to cocaine varied among individual animals, which was not due to individual differences in the reuptake of DA and 5-HT, but rather to individual differences in their vesicular release. Furthermore, we found that reserpine-induced depletion of storage vesicles reduced both short and long access cocaine self-administration, and the degree of reduction was linked to the vesicular storage capacity of the animals. In conclusion, we demonstrate a novel mechanism by which cocaine increases the extracellular concentrations of accumbal DA and 5-HT, namely via release from storage vesicles. Furthermore, individual differences in cocaine-induced vesicular monoamine release shape individual differences in not only the acute behavioral and neurochemical effects of the stimulant, but also in its intake. Thus, intracellular storage vesicles represent an attractive novel drug target to combat psychostimulant addiction.

neuroscience↗