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 to understand the biological bases of typical and atypical brain asymmetry but also warrants caution as asymmetry patterns seem to differ between humans and mice.

Serotonin transporter knockout in rats reduces beta- and gamma-band functional connectivity between the orbitofrontal cortex and amygdala during auditory discrimination.

The orbitofrontal cortex and amygdala collaborate in outcome-guided decision-making through reciprocal projections. While serotonin transporter knockout (SERT-/-) rodents show changes in outcome-guided decision-making, and in orbitofrontal cortex and amygdala neuronal activity, it remains unclear whether SERT genotype modulates orbitofrontal cortex-amygdala synchronization. We trained SERT-/- and SERT+/+ male rats to execute a task requiring to discriminate between two auditory stimuli, one predictive of a reward (CS+) and the other not (CS-), by responding through nose pokes in opposite-side ports. Overall, task acquisition was not influenced by genotype. Next, we simultaneously recorded local field potentials in the orbitofrontal cortex and amygdala of both hemispheres while the rats performed the task. Behaviorally, SERT-/- rats showed a nonsignificant trend for more accurate responses to the CS-. Electrophysiologically, orbitofrontal cortex-amygdala synchronization in the beta and gamma frequency bands during response selection was significantly reduced and associated with decreased hubness and clustering coefficient in both regions in SERT-/- rats compared to SERT+/+ rats. Conversely, theta synchronization at the time of behavioral response in the port associated with reward was similar in both genotypes. Together, our findings reveal the modulation by SERT genotype of the orbitofrontal cortex-amygdala functional connectivity during an auditory discrimination task.

Conditioned morphine tolerance promotes neurogenesis, dendritic remodelling and pro-plasticity molecules in the adult rat hippocampus.

Structural neuroplasticity of the hippocampus in the form of neurogenesis and dendritic remodelling underlying morphine tolerance is still less known. Therefore, in this study, we aimed to assess whether unconditioned- and conditioned-morphine tolerance can trigger structural neuroplasticity in the dorsal and ventral parts of the adult male rat hippocampus. Evaluation of the levels of neurogenesis markers (Ki67 and DCX) by immunohistochemistry shows that conditioned morphine tolerance is sufficient to increase the baseline topographic level of hippocampal neurogenesis in adult rats. Dendritic spine visualization by Golgi staining shows that the behavioural testing paradigms themselves are sufficient to trigger the hippocampus subregion-specific changes in the dendritic remodelling along the apical dendrites of hippocampal CA1 pyramidal neurons and dentate granule cells in adult rats. Quantitative reverse transcription polymerase chain reaction of Bdnf, Trkb, Rac-1 and RhoA mRNA levels as pro-plasticity molecules, shows that the conditioned morphine tolerance is effective in changing Bdnf and RhoA mRNA levels in the ventral hippocampus of adult rats. In summary, we demonstrate that the acquisition of morphine tolerance promotes adult neurogenesis, dendritic remodelling and pro-plasticity molecules such as Bdnf/Trkb in the rat hippocampus. Indeed, the structural neuroplasticity of the hippocampus may underlie the newly formed aberrant memory and could provide the initial basis for understanding the neurobiological mechanisms of morphine-tolerance plasticity in the hippocampus.

A neural model of vulnerability and resilience to stress-related disorders linked to differential susceptibility.

Expert opinion remains divided concerning the impact of putative risk factors on vulnerability to depression and other stress-related disorders. A large body of literature has investigated gene by environment interactions, particularly between the serotonin transporter polymorphism (5-HTTLPR) and negative environments, on the risk for depression. However, fewer studies have simultaneously investigated the outcomes in both negative and positive environments, which could explain some of the inconclusive findings. This is embodied by the concept of differential susceptibility, i.e., the idea that certain common gene polymorphisms, prenatal factors, and traits make some individuals not only disproportionately more susceptible and responsive to negative, vulnerability-promoting environments, but also more sensitive and responsive to positive, resilience-enhancing environmental conditions. Although this concept from the field of developmental psychology is well accepted and supported by behavioral findings, it is striking that its implementation in neuropsychiatric research is limited and that underlying neural mechanisms are virtually unknown. Based on neuroimaging studies that examined how factors mediating differential susceptibility affect brain function, we posit that environmental sensitivity manifests in increased salience network activity, increased salience and default mode network connectivity, and increased salience and central executive network connectivity. These changes in network function may bring about automatic exogenous attention for positive and negative stimuli and flexible attentional set-shifting. We conclude with a call to action; unraveling the neural mechanisms through which differential susceptibility factors mediate vulnerability and resilience may lead us to personalized preventive interventions.

Dopamine transporter silencing in the rat: systems-level alterations in striato-cerebellar and prefrontal-midbrain circuits.

Silencing of dopamine transporter (DAT), a main controlling factor of dopaminergic signaling, results in biochemical and behavioral features characteristic for neuropsychiatric diseases with presumed hyperdopaminergia including schizophrenia, attention deficit hyperactivity disorder (ADHD), bipolar disorder, and obsessive-compulsive disorder (OCD). Investigation of DAT silencing thus provides a transdiagnostic approach towards a systems-level understanding of common underlying pathways. Using a high-field multimodal imaging approach and a highly sensitive cryogenic coil, we integrated structural, functional and metabolic investigations in tandem with behavioral assessments on a newly developed preclinical rat model, comparing DAT homozygous knockout (DAT-KO, N = 14), heterozygous knockout (N = 8) and wild-type male rats (N = 14). We identified spatially distributed structural and functional brain alterations encompassing motor, limbic and associative loops that demonstrated strong behavioral relevance and were highly consistent across imaging modalities. DAT-KO rats manifested pronounced volume loss in the dorsal striatum, negatively correlating with cerebellar volume increase. These alterations were associated with hyperlocomotion, repetitive behavior and loss of efficient functional small-world organization. Further, prefrontal and midbrain regions manifested opposite changes in functional connectivity and local network topology. These prefrontal disturbances were corroborated by elevated myo-inositol levels and increased volume. To conclude, our imaging genetics approach provides multimodal evidence for prefrontal-midbrain decoupling and striato-cerebellar neuroplastic compensation as two key features of constitutive DAT blockade, proposing them as transdiagnostic mechanisms of hyperdopaminergia. Thus, our study connects developmental DAT blockade to systems-level brain changes, underlying impaired action inhibition control and resulting in motor hyperactivity and compulsive-like features relevant for ADHD, schizophrenia and OCD.

Ndufs4 knockout mouse models of Leigh syndrome: pathophysiology and intervention.

Mitochondria are small cellular constituents that generate cellular energy (ATP) by oxidative phosphorylation (OXPHOS). Dysfunction of these organelles is linked to a heterogeneous group of multisystemic disorders, including diabetes, cancer, ageing-related pathologies and rare mitochondrial diseases. With respect to the latter, mutations in subunit-encoding genes and assembly factors of the first OXPHOS complex (complex I) induce isolated complex I deficiency and Leigh syndrome. This syndrome is an early-onset, often fatal, encephalopathy with a variable clinical presentation and poor prognosis due to the lack of effective intervention strategies. Mutations in the nuclear DNA-encoded NDUFS4 gene, encoding the NADH:ubiquinone oxidoreductase subunit S4 (NDUFS4) of complex I, induce 'mitochondrial complex I deficiency, nuclear type 1' (MC1DN1) and Leigh syndrome in paediatric patients. A variety of (tissue-specific) Ndufs4 knockout mouse models were developed to study the Leigh syndrome pathomechanism and intervention testing. Here, we review and discuss the role of complex I and NDUFS4 mutations in human mitochondrial disease, and review how the analysis of Ndufs4 knockout mouse models has generated new insights into the MC1ND1/Leigh syndrome pathomechanism and its therapeutic targeting.

The association between serotonin transporter availability and the neural correlates of fear bradycardia.

Susceptibility to stress-related psychopathology is associated with reduced expression of the serotonin transporter (5-HTT), particularly in combination with stress exposure. Aberrant physiological and neuronal responses to threat may underlie this increased vulnerability. Here, implementing a cross-species approach, we investigated the association between 5-HTT expression and the neural correlates of fear bradycardia, a defensive response linked to vigilance and action preparation. We tested this during threat anticipation induced by a well-established fear conditioning paradigm applied in both humans and rodents. In humans, we studied the effect of the common 5-HTT-linked polymorphic region (5-HTTLPR) on bradycardia and neural responses to anticipatory threat during functional magnetic resonance imaging scanning in healthy volunteers (n = 104). Compared with homozygous long-allele carriers, the 5-HTTLPR short-allele carriers displayed an exaggerated bradycardic response to threat, overall reduced activation of the medial prefrontal cortex (mPFC), and increased threat-induced connectivity between the amygdala and periaqueductal gray (PAG), which statistically mediated the effect of the 5-HTTLPR genotype on bradycardia. In parallel, 5-HTT knockout (KO) rats also showed exaggerated threat-related bradycardia and behavioral freezing. Immunohistochemistry indicated overall reduced activity of glutamatergic neurons in the mPFC of KO rats and increased activity of central amygdala somatostatin-positive neurons, putatively projecting to the PAG, which-similarly to the human population-mediated the 5-HTT genotype's effect on freezing. Moreover, the ventrolateral PAG of KO rats displayed elevated overall activity and increased relative activation of CaMKII-expressing projection neurons. Our results provide a mechanistic explanation for previously reported associations between 5-HTT gene variance and a stress-sensitive phenotype.

Peripheral Serotonin Deficiency Affects Anxiety-like Behavior and the Molecular Response to an Acute Challenge in Rats.

Serotonin is synthetized through the action of tryptophan hydroxylase (TPH) enzymes. While the TPH2 isoform is responsible for the production of serotonin in the brain, TPH1 is expressed in peripheral organs. Interestingly, despite its peripheral localization, alterations of the gene coding for TPH1 have been related to stress sensitivity and an increased susceptibility for psychiatric pathologies. On these bases, we took advantage of newly generated TPH1-/- rats, and we evaluated the impact of the lack of peripheral serotonin on the behavior and expression of brain plasticity-related genes under basal conditions and in response to stress. At a behavioral level, TPH1-/- rats displayed reduced anxiety-like behavior. Moreover, we found that neuronal activation, quantified by the expression of Bdnf and the immediate early gene Arc and transcription of glucocorticoid responsive genes after 1 h of acute restraint stress, was blunted in TPH1-/- rats in comparison to TPH1+/+ animals. Overall, we provided evidence for the influence of peripheral serotonin levels in modulating brain functions under basal and dynamic situations.

The role of the serotonin transporter in prefrontal cortex glutamatergic signaling following short- and long-access cocaine self-administration.

Vulnerability to drug addiction relies on substantial individual differences. We previously demonstrated that serotonin transporter knockout (SERT-/- ) rats show increased cocaine intake and develop signs of compulsivity. However, the underlying neural mechanisms are not fully understood. Given the pivotal role of glutamate and prefrontal cortex in cocaine-seeking behavior, we sought to investigate the expression of proteins implicated in glutamate neurotransmission in the prefrontal cortex of naïve and cocaine-exposed rats lacking SERT. We focused on the infralimbic (ILc) and prelimbic (PLc) cortices, which are theorized to exert opposing effects on the control over subcortical brain areas. SERT-/- rats, which compared to wild-type (SERT+/+ ) rats show increased ShA and LgA intake short-access (ShA) and long-access (LgA) cocaine intake, were sacrificed 24 h into withdrawal for ex vivo molecular analyses. In the ILc homogenate of SERT-/- rats, we observed a sharp increase in glial glutamate transporter 1 (GLT-1) after ShA, but not LgA, cocaine intake. This was paralleled by ShA-induced increases in GluN1, GluN2A, and GluN2B NMDA receptor subunits and their scaffolding protein SAP102 in the ILc homogenate, but not postsynaptic density, of these knockout animals. In the PLc, we found no major changes in the homogenate; conversely, the expression of GluN1 and GluN2A NMDA receptor subunits was increased in the postsynaptic density under ShA conditions and reduced under LgA conditions. These results point to SERT as a critical regulator of glutamate homeostasis in a way that differs between the subregions investigated, the duration of cocaine exposure as well as the cellular compartment analyzed.

Fear Extinction and Predictive Trait-Like Inter-Individual Differences in Rats Lacking the Serotonin Transporter.

Anxiety disorders are associated with a failure to sufficiently extinguish fear memories. The serotonergic system (5-hydroxytryptamine, 5-HT) with the 5-HT transporter (5-HTT, SERT) is strongly implicated in the regulation of anxiety and fear. In the present study, we examined the effects of SERT deficiency on fear extinction in a differential fear conditioning paradigm in male and female rats. Fear-related behavior displayed during acquisition, extinction, and recovery, was measured through quantification of immobility and alarm 22-kHz ultrasonic vocalizations (USV). Trait-like inter-individual differences in novelty-seeking, anxiety-related behavior, habituation learning, cognitive performance, and pain sensitivity were examined for their predictive value in forecasting fear extinction. Our results show that SERT deficiency strongly affected the emission of 22-kHz USV during differential fear conditioning. During acquisition, extinction, and recovery, SERT deficiency consistently led to a reduction in 22-kHz USV emission. While SERT deficiency did not affect immobility during acquisition, genotype differences started to emerge during extinction, and during recovery rats lacking SERT showed higher levels of immobility than wildtype littermate controls. Recovery was reflected in increased levels of immobility but not 22-kHz USV emission. Prominent sex differences were evident. Among several measures for trait-like inter-individual differences, anxiety-related behavior had the best predictive quality.

BDNF Overexpression in the Ventral Hippocampus Promotes Antidepressant- and Anxiolytic-Like Activity in Serotonin Transporter Knockout Rats.

BDNF plays a pivotal role in neuroplasticity events, vulnerability and resilience to stress-related disorders, being decreased in depressive patients and increased after antidepressant treatment. BDNF was found to be reduced in 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 of depression in humans. They present decreased BDNF levels, and anxiety- and depression-like behavior. To investigate whether upregulating BDNF would ameliorate the phenotype of SERT-/- rats, we overexpressed BDNF locally into the ventral hippocampus and submitted the animals to behavioral testing. The results showed that BDNF overexpression in the vHIP of SERT-/- rats promoted higher sucrose preference and sucrose intake; on the first day of the sucrose consumption test it decreased immobility time in the forced swim test and increased the time spent in the center of a novel environment. Furthermore, BDNF overexpression altered social behavior in SERT-/- rats, which presented increased passive contact with test partner and decreased solitary behavior. Finally, it promoted decrease in plasma corticosterone levels 60 min 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 target to new therapeutic approaches to improve depressive symptoms.

Ultrahigh-resolution MRI reveals structural brain differences in serotonin transporter knockout rats after sucrose and cocaine self-administration.

Excessive use of cocaine is known to induce changes in brain white and gray matter. It is unknown whether the extent of these changes is related to individual differences in vulnerability to cocaine addiction. One factor increasing vulnerability involves reduced expression of the serotonin transporter (5-HTT). Human studies have shown that inherited 5-HTT downregulation is associated with structural changes in the brain. These genotype-related structural changes may contribute to risk for cocaine addiction. Here, we tested this idea by using ultrahigh-resolution structural magnetic resonance imaging (MRI) on postmortem tissue of 5-HTT-/- and wild-type (5-HTT+/+ ) rats with a history of long access to cocaine or sucrose (control) self-administration. We found that 5-HTT-/- rats, compared with wild-type control animals, self-administered more cocaine, but not sucrose, under long-access conditions. Ultrahigh-resolution structural MRI subsequently revealed that, independent of sucrose or cocaine self-administration, 5-HTT-/- rats had a smaller amygdala. Moreover, we found an interaction between genotype and type of reward for dorsal raphe nucleus volume. The data point to an important but differential role of the amygdala and dorsal raphe nucleus in 5-HTT genotype-dependent vulnerability to cocaine addiction.

Gestational Factors throughout Fetal Neurodevelopment: The Serotonin Link.

Serotonin (5-HT) is a critical player in brain development and neuropsychiatric disorders. Fetal 5-HT levels can be influenced by several gestational factors, such as maternal genotype, diet, stress, medication, and immune activation. In this review, addressing both human and animal studies, we discuss how these gestational factors affect placental and fetal brain 5-HT levels, leading to changes in brain structure and function and behavior. We conclude that gestational factors are able to interact and thereby amplify or counteract each other's impact on the fetal 5-HT-ergic system. We, therefore, argue that beyond the understanding of how single gestational factors affect 5-HT-ergic brain development and behavior in offspring, it is critical to elucidate the consequences of interacting factors. Moreover, we describe how each gestational factor is able to alter the 5-HT-ergic influence on the thalamocortical- and prefrontal-limbic circuitry and the hypothalamo-pituitary-adrenocortical-axis. These alterations have been associated with risks to develop attention deficit hyperactivity disorder, autism spectrum disorders, depression, and/or anxiety. Consequently, the manipulation of gestational factors may be used to combat pregnancy-related risks for neuropsychiatric disorders.

Alterations of Glutamatergic Markers in the Prefrontal Cortex of Serotonin Transporter Knockout Rats: A Developmental Timeline.

The serotoninergic system plays a key role in environmental sensitivity, potentially through down-stream effects on the GABAergic and glutamatergic systems. We previously demonstrated that juvenile serotonin transporter knockout (SERT-/-) rats, showing increased environmental sensitivity, exhibit a decreased GABA-mediated inhibitory tone in the cortex. Since the GABAergic and glutamatergic systems are tightly interconnected, we here analyzed glutamatergic markers in the prefrontal cortex of SERT-/- rats, from the early stages of life until adulthood. We found that SERT inactivation in pre-weaning, juvenile, and adult rats was associated with reduced expression of proteins essential for the glutamatergic synapses such as GluN1, PSD95, CDC42, and SEPT7. These lifelong molecular changes may destabilize glutamatergic signaling and possibly contribute to stress sensitivity and vulnerability to stress-related disorders associated with SERT alteration.

Histamine-4 receptor antagonist JNJ7777120 inhibits pro-inflammatory microglia and prevents the progression of Parkinson-like pathology and behaviour in a rat model.

The activation of microglial cells is presumed to play a key role in the pathogenesis of Parkinson's disease (PD). The activity of microglia is regulated by the histamine-4 receptor (H4R), thus providing a novel target that may prevent the progression of PD. However, this putative mechanism has so far not been validated. In our previous study, we found that mRNA expression of H4R was upregulated in PD patients. In the present study, we validated this possible mechanism using the rotenone-induced PD rat model, in which mRNA expression levels of H4R-, and microglial markers were significantly increased in the ventral midbrain. Inhibition of H4R in rotenone-induced PD rat model by infusion of the specific H4R antagonist JNJ7777120 into the lateral ventricle resulted in blockade of microglial activation. In addition, pharmacological targeting of H4R in rotenone-lesioned rats resulted in reduced apomorphine-induced rotational behaviour, prevention of dopaminergic neuron degeneration and associated decreases in striatal dopamine levels. These changes were accompanied by a reduction of Lewy body-like neuropathology. Our results provide first proof of the efficacy of an H4R antagonist in a commonly used PD rat model, and proposes the H4R as a promising target to clinically tackle microglial activation and thereby the progression of PD.

Transcriptome Analysis Identifies Multifaceted Regulatory Mechanisms Dictating a Genetic Switch from Neuronal Network Establishment to Maintenance During Postnatal Prefrontal Cortex Development.

The prefrontal cortex (PFC) is one of the latest brain regions to mature, which allows the acquisition of complex cognitive abilities through experience. To unravel the underlying gene expression changes during postnatal development, we performed RNA-sequencing (RNA-seq) in the rat medial PFC (mPFC) at five developmental time points from infancy to adulthood, and analyzed the differential expression of protein-coding genes, long intergenic noncoding RNAs (lincRNAs), and alternative exons. We showed that most expression changes occur in infancy, and that the number of differentially expressed genes reduces toward adulthood. We observed 137 differentially expressed lincRNAs and 796 genes showing alternative exon usage during postnatal development. Importantly, we detected a genetic switch from neuronal network establishment in infancy to maintenance of neural networks in adulthood based on gene expression dynamics, involving changes in protein-coding and lincRNA gene expression as well as alternative exon usage. Our gene expression datasets provide insights into the multifaceted transcriptional regulation of the developing PFC. They can be used to study the basic developmental processes of the mPFC and to understand the mechanisms of neurodevelopmental and neuropsychiatric disorders. Our study provides an important contribution to the ongoing efforts to complete the "brain map", and to the understanding of PFC development.

Increased cocaine self-administration in rats lacking the serotonin transporter: a role for glutamatergic signaling in the habenula.

Serotonin (5-HT) and the habenula (Hb) contribute to motivational and emotional states such as depression and drug abuse. The dorsal raphe nucleus, where 5-HT neurons originate, and the Hb are anatomically and reciprocally interconnected. Evidence exists that 5-HT influences Hb glutamatergic transmission. Using serotonin transporter knockout (SERT-/- ) rats, which show depression-like behavior and increased cocaine intake, we investigated the effect of SERT reduction on expression of genes involved in glutamate neurotransmission under both baseline conditions as well as after short-access or long-access cocaine (ShA and LgA, respectively) intake. In cocaine-naïve animals, SERT removal led to reduced baseline Hb mRNA levels of critical determinants of glutamate transmission, such as SLC1A2, the main glutamate transporter and N-methyl-D-aspartate (Grin1, Grin2A and Grin2B) as well as α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (Gria1 and Gria2) receptor subunits, with no changes in the scaffolding protein Dlg4. In response to ShA and LgA cocaine intake, SLC1A2 and Grin1 mRNA levels decreased in SERT+/+ rats to levels equal of those of SERT-/- rats. Our data reveal that increased extracellular levels of 5-HT modulate glutamate neurotransmission in the Hb, serving as critical neurobiological substrate for vulnerability to cocaine addiction.

Appetitive to aversive counter-conditioning as intervention to reduce reinstatement of reward-seeking behavior: the role of the serotonin transporter.

Counter-conditioning can be a valid strategy to reduce reinstatement of reward-seeking behavior. However, this has not been tested in laboratory animals with extended cocaine-taking backgrounds nor is it well understood, which individual differences may contribute to its effects. Here, we set out to investigate the influence of serotonin transporter (5-HTT) genotype on the effectiveness of counter-conditioning after extended access to cocaine self-administration. To this end, 5-HTT+/+ and 5-HTT-/- rats underwent a touch screen-based approach to test if reward-induced reinstatement of responding to a previously counter-conditioned cue is reduced, compared with a non-counter-conditioned cue, in a within-subject manner. We observed an overall extinction deficit of cocaine-seeking behavior in 5-HTT-/- rats and a resistance to punishment during the counter-conditioning session. Furthermore, we observed a significant decrease in reinstatement to cocaine and sucrose associated cues after counter-conditioning but only in 5-HTT+/+ rats. In short, we conclude that the paradigm we used was able to produce effects of counter-conditioning of sucrose seeking behavior in line with what is described in literature, and we demonstrate that it can be effective even after long-term exposure to cocaine, in a genotype-dependent manner.

Reduced Inhibition within Layer IV of Sert Knockout Rat Barrel Cortex is Associated with Faster Sensory Integration.

Neural activity is essential for the maturation of sensory systems. In the rodent primary somatosensory cortex (S1), high extracellular serotonin (5-HT) levels during development impair neural transmission between the thalamus and cortical input layer IV (LIV). Rodent models of impaired 5-HT transporter (SERT) function show disruption in their topological organization of S1 and in the expression of activity-regulated genes essential for inhibitory cortical network formation. It remains unclear how such alterations affect the sensory information processing within cortical LIV. Using serotonin transporter knockout (Sert-/-) rats, we demonstrate that high extracellular serotonin levels are associated with impaired feedforward inhibition (FFI), fewer perisomatic inhibitory synapses, a depolarized GABA reversal potential and reduced expression of KCC2 transporters in juvenile animals. At the neural population level, reduced FFI increases the excitatory drive originating from LIV, facilitating evoked representations in the supragranular layers II/III. The behavioral consequence of these changes in network excitability is faster integration of the sensory information during whisker-based tactile navigation, as Sert-/- rats require fewer whisker contacts with tactile targets and perform object localization with faster reaction times. These results highlight the association of serotonergic homeostasis with formation and excitability of sensory cortical networks, and consequently with sensory perception.

Maternal depressive symptoms during pregnancy are associated with amygdala hyperresponsivity in children.

Depression during pregnancy is highly prevalent and has a multitude of potential risks of the offspring. Among confirmed consequences is a higher risk of psychopathology. However, it is unknown how maternal depression may impact the child's brain to mediate this vulnerability. Here we studied amygdala functioning, using task-based functional MRI, in children aged 6-9 years as a function of prenatal maternal depressive symptoms selected from a prospective population-based sample (The Generation R Study). We show that children exposed to clinically relevant maternal depressive symptoms during pregnancy (N = 19) have increased amygdala responses to negative emotional faces compared to control children (N = 20) [F(1,36) 7.02, p = 0.022]. Strikingly, postnatal maternal depressive symptoms, obtained at 3 years after birth, did not explain this relation. Our findings are in line with a model in which prenatal depressive symptoms of the mother are associated with amygdala hyperresponsivity in her offspring, which may represent a risk factor for later-life psychopathology.