A new mouse line reporting the translation of brain-derived neurotrophic factor using green fluorescent protein

While BDNF is receiving considerable attention for its role in synaptic plasticity and in nervous system dysfunction, identifying brain circuits involving BDNF-expressing neurons has been challenging. BDNF levels are very low in most brain areas, except for the large mossy fiber terminals in the hippocampus where BDNF accumulates at readily detectable levels. This report describes the generation of a mouse line allowing the detection of single brain cells synthesizing BDNF. A bicistronic construct encoding BDNF tagged with a P2A sequence preceding GFP allows the translation of BDNF and GFP as separate proteins. Following its validation with transfected cells, this construct was used to replace the endogenous Bdnf gene. Viable and fertile homozygote animals were generated, with the GFP signal marking neuronal cell bodies translating the Bdnf mRNA. Importantly, the distribution of immunoreactive BDNF remained unchanged, as exemplified by its accumulation in mossy fiber terminals in the transgenic animals. GFP-labeled neurons could be readily visualized in distinct layers in the cerebral cortex where BDNF has been difficult to detect with currently available reagents. In the hippocampal formation, quantification of the GFP signal revealed that <10% of the neurons do not translate the Bdnf mRNA at detectable levels, with the highest proportion of strongly labeled neurons found in CA3

Investigating neuropsychological and reward-related deficits in a chronic corticosterone-induced model of depression

Chronic stress is a known risk factor for the development of major depression (MDD) and is commonly used to induce a depression-like phenotype in rodents. Similar phenotypic effects are also observed in rodents when treated chronically with the stress hormone corticosterone. In this study, we investigated the neuropsychological consequences of chronic corticosterone treatment in male rats using two translational rodent assays of affective bias, the judgement bias task (JBT) and affective bias test (ABT). We also used the reward learning assay (RLA) and sucrose preference test (SPT) to quantify reward-related behaviours. Negative biases in decision-making were observed in the chronic corticosterone-treated group but only when the treatment was given shortly before each behavioural session. The same dose of corticosterone, when given daily after completion of the behavioural session had no effects. Chronic corticosterone treatment did not potentiate negative affective biases in the ABT induced by either an acute pharmacological or stress manipulation but both reward learning and reward sensitivity were blunted. Analysis of the brain tissue from animals receiving chronic corticosterone found reduced hippocampal neurogenesis consistent with previous studies suggesting corticosterone-induced neurotrophic deficits. Taken together, these data suggest chronic corticosterone treatment induces neuropsychological effects related to changes in reward learning, memory and negative biases in decision making, but these decision-making biases depend on whether rewarding outcomes were experienced during the acute effects of the drug. These findings suggest an important interaction between psychological and biological factors resulting in negative biases in decision-making in this model

Cross-site reproducibility of social deficits in group-housed BTBR mice using automated longitudinal behavioural monitoring

Social withdrawal is associated with a variety of neuropsychiatric disorders, including neurodevelopmental disorders. Rodent studies provide the opportunity to study neurobiological mechanisms underlying social withdrawal, however, homologous paradigms to increase translatability of social behaviour between human and animal observation are needed. Standard behavioural rodent assays have limited ethological validity in terms of number of interaction partners, type of behaviour, duration of observation and environmental conditions. In addition, reproducibility of behavioural findings in rodents is further limited by manual and subjective behavioural scoring. Using a newly developed automated tracking tool for longitudinal monitoring of freely moving mice, we assessed social behaviours (approach, sniff, follow and leave) over seven consecutive days in colonies of BTBR and of C57BL/6J mice in two independent laboratories. Results from both laboratories confirmed previous findings of reduced social interaction in BTBR mice revealing a high level of reproducibility for this mouse phenotype using longitudinal colony assessments. In addition, we showed that detector settings contribute to laboratory specific findings as part of the behavioural data analysis procedure. Our cross-site study demonstrates reproducibility and robustness of reduced social interaction in BTBR mice using automated analysis in an ethologically relevant context

The reverse translation of a quantitative neuropsychiatric framework into preclinical studies:Focus on social interaction and behavior

Following the Research Domain Criteria (RDoC) concept, major brain circuits are conserved in evolution and malfunctioning of a brain circuit will lead to specific behavioral symptoms. Reverse translation of patient-based findings from Alzheimer’s disease (AD), schizophrenia (SZ) and major depression (MD) patients to preclinical models accordingly can be a starting point for developing a deeper understanding of the functional circuit biology and contribute to the validation of new hypotheses for therapeutic intervention in patients. In the context of the EU funded PRISM project, a preclinical test battery of tasks has been selected and aligned with the clinical test battery. It allows for assessment of social functioning, sensory processing, attention and working memory and is designed for validation of biological substrates from human molecular landscaping of social withdrawal. This review will broadly summarize the available literature on tasks for studying social behavior in rodents and outline the development of a preclinical test battery for the PRISM project by reverse translation

Chronic Social Stress Leads to Reduced Gustatory Reward Salience and Effort Valuation in Mice

Pathology of reward processing is a major clinical feature of stress-related neuropsychiatric disorders including depression. Several dimensions of reward processing can be impacted, including reward valuation/salience, learning, expectancy and effort valuation. To establish the causal relationships between stress, brain changes, and reward processing pathologies, valid animal models are essential. Here, we present mouse experiments investigating behavioral effects of chronic social stress (CSS) in association learning tests of gustatory reward salience and effort valuation. The reward salience test (RST) comprised Pavlovian pairing of a tone with gustatory reward. The effort valuation test (EVT) comprised operant responding for gustatory reinforcement on a progressive ratio schedule (PRS). All testing was conducted with mice at 100% baseline body weight (BBW). In one experiment, mice underwent 15-day CSS or control handling (CON) and testing was conducted using sucrose pellets. In the RST on days 16–17, CSS mice made fewer feeder responses and had a longer tone response latency, than CON mice. In a shallow EVT on days 19–20, CSS mice attained a lower final ratio than CON mice. In a second CSS experiment, mice underwent CSS or CON and testing was conducted with chocolate pellets and in the presence of standard diet (low effort/low reward). In the RST on days 16–18, CSS mice made fewer feeder responses and had a longer tone response latency, than CON mice. In a steep EVT on days 19–20, CSS and CON mice attained less pellets than in the RST, and CSS mice attained a lower final ratio than CON mice. At day 21, blood levels of glucose and the satiety adipokine leptin were similar in CSS and CON mice. Therefore, CSS leads to consistent reductions in reward salience and effort valuation in tests based on association learning. These reward pathology models are being applied to identify the underlying neurobiology and putative molecular targets for therapeutic pharmacology

Stress deficits in reward behaviour are associated with and replicated by dysregulated amygdala-nucleus accumbens pathway function in mice

Reduced reward interest/learning and reward-to-effort valuation are distinct, common symptoms in neuropsychiatric disorders for which chronic stress is a major aetiological factor. Glutamate neurons in basal amygdala (BA) project to various regions including nucleus accumbens (NAc). The BA-NAc neural pathway is activated by reward and aversion, with many neurons being monovalent. In adult male mice, chronic social stress (CSS) leads to reduced discriminative reward learning (DRL) associated with decreased BA-NAc activity, and to reduced reward-to-effort valuation (REV) associated, in contrast, with increased BA-NAc activity. Chronic tetanus toxin BA-NAc inhibition replicates the CSS-DRL effect and causes a mild REV reduction, whilst chronic DREADDs BA-NAc activation replicates the CSS effect on REV without affecting DRL. This study provides evidence that stress disruption of reward processing involves the BA-NAc neural pathway; the bi-directional effects implicate opposite activity changes in reward (learning) neurons and aversion (effort) neurons in the BA-NAc pathway following chronic stress

Rapid-acting antidepressant drugs modulate affective bias in rats

How rapid-acting antidepressants (RAADs), such as ketamine, induce immediate and sustained improvements in mood in patients with major depressive disorder (MDD) is poorly understood. A core feature of MDD is the prevalence of cognitive processing biases associated with negative affective states, and the alleviation of negative affective biases may be an index of response to drug treatment. Here, we used an affective bias behavioral test in rats, based on an associative learning task, to investigate the effects of RAADs. To generate an affective bias, animals learned to associate two different digging substrates with a food reward in the presence or absence of an affective state manipulation. A choice between the two reward-associated digging substrates was used to quantify the affective bias generated. Acute treatment with the RAADs ketamine, scopolamine, or psilocybin selectively attenuated a negative affective bias in the affective bias test. Low, but not high, doses of ketamine and psilocybin reversed the valence of the negative affective bias 24 hours after RAAD treatment. Only treatment with psilocybin, but not ketamine or scopolamine, led to a positive affective bias that was dependent on new learning and memory formation. The relearning effects of ketamine were dependent on protein synthesis localized to the rat medial prefrontal cortex and could be modulated by cue reactivation, consistent with experience-dependent neural plasticity. These findings suggest a neuropsychological mechanism that may explain both the acute and sustained effects of RAADs, potentially linking their effects on neural plasticity with affective bias modulation in a rodent model

Riluzole Attenuates L-DOPA-Induced Abnormal Involuntary Movements Through Decreasing CREB1 Activity

Chronic administration of L-DOPA, the first-line treatment of dystonic symptoms in childhood or in Parkinson's disease, often leads to the development of abnormal involuntary movements (AIMs), which represent an important clinical problem. Although it is known that Riluzole attenuates L-DOPA-induced AIMs, the molecular mechanisms underlying this effect are not understood. Therefore, we studied the behavior and performed RNA sequencing of the striatum in three groups of rats that all received a unilateral lesion with 6-hydroxydopamine in their medial forebrain bundle, followed by the administration of saline, L-DOPA, or L-DOPA combined with Riluzole. First, we provide evidence that Riluzole attenuates AIMs in this rat model. Subsequently, analysis of the transcriptomics data revealed that Riluzole is predicted to reduce the activity of CREB1, a transcription factor that regulates the expression of multiple proteins that interact in a molecular landscape involved in apoptosis. Although this mechanism underlying the beneficial effect of Riluzole on AIMs needs to be confirmed, it provides clues towards novel or existing compounds for the treatment of AIMs that modulate the activity of CREB1 and, hence, its downstream targets