Supramammillary neurons projecting to the septum regulate dopamine and motivation for environmental interaction in mice.

The supramammillary region (SuM) is a posterior hypothalamic structure, known to regulate hippocampal theta oscillations and arousal. However, recent studies reported that the stimulation of SuM neurons with neuroactive chemicals, including substances of abuse, is reinforcing. We conducted experiments to elucidate how SuM neurons mediate such effects. Using optogenetics, we found that the excitation of SuM glutamatergic (GLU) neurons was reinforcing in mice; this effect was relayed by their projections to septal GLU neurons. SuM neurons were active during exploration and approach behavior and diminished activity during sucrose consumption. Consistently, inhibition of SuM neurons disrupted approach responses, but not sucrose consumption. Such functions are similar to those of mesolimbic dopamine neurons. Indeed, the stimulation of SuM-to-septum GLU neurons and septum-to-ventral tegmental area (VTA) GLU neurons activated mesolimbic dopamine neurons. We propose that the supramammillo-septo-VTA pathway regulates arousal that reinforces and energizes behavioral interaction with the environment.

Identification of serum N-glycoproteins as a biological correlate underlying chronic stress response in mice.

Glycosylation is a post-translational protein modification in eukaryotes and plays an important role in controlling several diseases. N-glycan structure is emerging as a new paradigm for biomarker discovery of neuropsychiatric disorders. However, the relationship between N-glycosylation pattern and depression is not well elucidated to date. This study aimed to explore whether serum N-glycan structures are altered in depressive-like behavior using a stress based mouse model. We used two groups of BALB/c mice; (i) treated group exposed to chronic unpredictable mild stress (CUMS) as a model of depression, and (ii) control group. Behavioral tests in mice (e.g., sucrose preference test, forced swimming test, and fear conditioning test) were used to evaluate the threshold level to which mice displayed a depressive-like phenotype. Serum N-glycans were analyzed carefully using glycoblotting followed by Matrix-assisted laser desorption ionization-time of flight/mass spectrometry (MALDI-TOF/MS) to exhibit N-glycan expression levels and to illustrate the changes in the N-glycome profile. N-glycan expression levels were commonly altered in the depressive-like model and correlated well with the behavioral data. Our results indicated that sialylated N-glycan was identified as a biomarker associated with depressive symptoms, which may have utility as a candidate biomarker for the clinical diagnosis and monitoring of depression.

Identification of multiple genetic loci in the mouse controlling immobility time in the tail suspension and forced swimming tests.

Depression is one of the most famous psychiatric disorders in humans in all over the countries and considered a complex neurobehavioral trait and difficult to identify causal genes. Tail suspension test (TST) and forced swimming test (FST) are widely used for assessing depression-like behavior and antidepressant activity in mice. A variety of antidepressant agents are known to reduce immobility time in both TST and FST. To identify genetic determinants of immobility duration in both tests, we analyzed 101 F2 mice from an intercross between C57BL/6 and DBA/2 strains. Quantitative trait locus (QTL) mapping using 106 microsatellite markers revealed three loci (two significant and one suggestive) and five suggestive loci controlling immobility time in the TST and FST, respectively. Results of QTL analysis suggest a broad description of the genetic architecture underlying depression, providing underpinnings for identifying novel molecular targets for antidepressants to clear the complex genetic mechanisms of depressive disorders.