Regional gene expression signatures are associated with sex-specific functional connectivity changes in depression.

The neural substrates of depression may differ in men and women, but the underlying mechanisms are incompletely understood. Here, we show that depression is associated with sex-specific patterns of abnormal functional connectivity in the default mode network and in five regions of interest with sexually dimorphic transcriptional effects. Regional differences in gene expression in two independent datasets explained the neuroanatomical distribution of abnormal connectivity. These gene sets varied by sex and were strongly enriched for genes implicated in depression, synapse function, immune signaling, and neurodevelopment. In an independent sample, we confirmed the prediction that individual differences in default mode network connectivity are explained by inferred brain expression levels for six depression-related genes, including PCDH8, a brain-specific protocadherin integral membrane protein implicated in activity-related synaptic reorganization. Together, our results delineate both shared and sex-specific changes in the organization of depression-related functional networks, with implications for biomarker development and fMRI-guided therapeutic neuromodulation.

Medial prefrontal cortex and anteromedial thalamus interaction regulates goal-directed behavior and dopaminergic neuron activity.

The prefrontal cortex is involved in goal-directed behavior. Here, we investigate circuits of the PFC regulating motivation, reinforcement, and its relationship to dopamine neuron activity. Stimulation of medial PFC (mPFC) neurons in mice activated many downstream regions, as shown by fMRI. Axonal terminal stimulation of mPFC neurons in downstream regions, including the anteromedial thalamic nucleus (AM), reinforced behavior and activated midbrain dopaminergic neurons. The stimulation of AM neurons projecting to the mPFC also reinforced behavior and activated dopamine neurons, and mPFC and AM showed a positive-feedback loop organization. We also found using fMRI in human participants watching reinforcing video clips that there is reciprocal excitatory functional connectivity, as well as co-activation of the two regions. Our results suggest that this cortico-thalamic loop regulates motivation, reinforcement, and dopaminergic neuron activity.

Intrinsic Brain Network Biomarkers of Antidepressant Response: a Review.

PURPOSE OF REVIEW: Poor treatment response is a hallmark of major depressive disorder. To tackle this problem, recent neuroimaging studies have sought to characterize antidepressant response in terms of pretreatment differences in intrinsic functional brain networks. Our aim is to review recent studies that predict antidepressant response using intrinsic network connectivity. We discuss current methodological limitations and directions for future antidepressant biomarker studies. RECENT FINDINGS: Functional connectivity stemming from the subgenual and rostral anterior cingulate has shown particular consistency in predicting antidepressant response. Differences in this connectivity may prove fruitful in differentiating treatment responders to many antidepressant interventions. Future biomarker studies should integrate biological MDD subtypes to address the disorder's inherent clinical heterogeneity. These clinical and scientific advancements have the potential to address this population marked by limited treatment response. Methodological considerations, including patient selection, response criteria, and model overfitting, will require future investigation to ensure that biomarkers generalize for prospective prediction of treatment response.

Interaction of chronic food restriction and methylphenidate in sensation seeking of rats.

RATIONALE: It is necessary to understand better how chronic food restriction (CFR) and psychostimulant drugs interact in motivated behavior unrelated to food or energy homeostasis. OBJECTIVES: We examined whether CFR augments methylphenidate (MPH)-potentiated responding reinforced by visual sensation (VS) and whether repeated MPH injections or prolonged CFR further augments such responses. METHODS: Before starting the following experiments, rats on a CFR diet received a limited daily ration in such a way that their body weights decreased to 85-90% of their original weights over 2 weeks. In experiment 1, rats on CFR and ad libitum diet received four injections of varying MPH doses (0, 2.5, 5, and 10 mg/kg). In experiment 2, CFR and ad libitum groups received repeated injections of MPH (2.5 mg/kg). In experiment 3, half of CFR rats received repeated injections of MPH (2.5 mg/kg), and the other half received saline, and following a 7-day abstinence, they all received the 2.5-mg/kg dose of MPH. RESULTS: CFR rats increased VS-reinforced responding more than ad libitum rats when they received MPH. Repeated injections of MPH with prolonged CFR further increased VS-reinforced responding. We found a double dissociation where prolonged CFR (3 vs. 6 weeks) made VS-reinforced responding, but not locomotor activity, more responsive to MPH, whereas repeated MPH injections made locomotor activity, but not VS-reinforced responding, more responsive to MPH. CONCLUSIONS: CFR markedly potentiates effects of MPH on VS-reinforced responding. The present study demonstrates that the longer CFR continues, the greater psychostimulant drugs augment behavioral interaction with salient stimuli.

Disrupting Glutamate Co-transmission Does Not Affect Acquisition of Conditioned Behavior Reinforced by Dopamine Neuron Activation.

Dopamine neurons in the ventral tegmental area (VTA) were previously found to express vesicular glutamate transporter 2 (VGLUT2) and to co-transmit glutamate in the ventral striatum (VStr). This capacity may play an important role in reinforcement learning. Although it is known that activation of the VTA-VStr dopamine system readily reinforces behavior, little is known about the role of glutamate co-transmission in such reinforcement. By combining electrode recording and optogenetics, we found that stimulation of VTA dopamine neurons in vivo evoked fast excitatory responses in many VStr neurons of adult mice. Whereas conditional knockout of the gene encoding VGLUT2 in dopamine neurons largely eliminated fast excitatory responses, it had little effect on the acquisition of conditioned responses reinforced by dopamine neuron activation. Therefore, glutamate co-transmission appears dispensable for acquisition of conditioned responding reinforced by DA neuron activation.