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. Summary 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.

Summary 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. While 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.

The lateral septum has strong efferent projections to hypothalamic and midbrain regions, and has been associated with modulation of social behavior, anxiety, fear conditioning, memory-related behaviors, and the mesolimbic reward pathways. Understanding natural variation of lateral septal anatomy and function, as well as its genetic modulation, may provide important insights into individual differences in these evolutionarily important functions. Here we address these issues by using efficient and unbiased stereological probes to estimate the volume of the lateral septum in the BXD line of recombinant inbred mice. Lateral septum volume is a highly variable trait, with a 2.5-fold difference among animals. We find that this trait covaries with a number of behavioral and physiological phenotypes, many of which have already been associated with behaviors modulated by the lateral septum, such as spatial learning, anxiety, and reward-seeking. Heritability of lateral septal volume is moderate (h 2 = 0.52), and much of the heritable variation is caused by a locus on the distal portion of chromosome (Chr) 1. Composite interval analysis identified a secondary interval on Chr 2 that works additively with the Chr 1 locus to increase lateral septum volume. Using bioinformatic resources, we identified plausible candidate genes in both intervals that may influence the volume of this key nucleus, as well as associated behaviors.