Research

Primary pathology of major depressive disorder

The goal of our human postmortem studies is to characterize the primary pathology in the brains of patients with depression. Armed with this information, we can then identify targets for subsequent mechanistic investigations. Specifically, we hypothesize that the biological liability to major depression is reflected in persistent molecular pathology within the corticolimbic network of mood regulation.

We recently reported that men and women with MDD not only have very distinct molecular pathology across the corticolimbic circuit of mood regulation but that many molecular changes were in the opposite directions.

Our analysis of men with MDD found reductions in markers of synaptic function and increases in markers of microglia and inflammation, consistent with reports of decreased pyramidal cell dendritic spine synapses and increased reactive microglia in depressed men. The molecular changes in MDD males are consistent with a model in which reactive microglia participate in excessive pathologic synapse removal.

Surprisingly, our analysis of women with MDD found increased markers of synaptic function coupled with decreased markers of immune function and microglia, which is exactly the opposite of depressed men. Together, these studies suggest pyramidal cells and microglia are affected in MDD, but in opposite directions in men and women.

Related publications:

Barko K, Shelton M, Sue X, Afriyie-Agyemang Y, Puig S, Freyberg Z, Tseng GC, Logan RW, Seney ML. Brain region- and sex-specific transcriptional profiles of microglia. Front Psychiatry. 2022. Aug24;12:945548. PMID: 36090351.

Seney ML, Nestler EJ. Introduction to Special Issue: Insight into Sex Differences in Neuropsychiatric Syndromes from Transcriptomic Analyses. Biol Psychiatry. 2022. Jan 1;91(1)3-5. PMID: 34857105.

Seney ML, Glausier J, Sibille E. Large-scale transcriptomics studies provide insight into sex differences in depression. Biol Psychiatry. 2022. Jan 1;91(1):14-24. PMID: 33648716.

Seney ML, Huo Z, Cahill K, French L, Puralewski R, Zhang J, Logan RW, Tseng G, Lewis DA, Sibille E. Opposite Molecular Signatures of Depression in Men and Women. Biol Psychiatry. 2018 Jul 1;84(1):18-27. PubMed PMID: 29548746; PubMed Central PMCID: PMC6014892.

Douillard-Guilloux G, Lewis D, Seney ML, Sibille E. Decrease in somatostatin-positive cell density in the amygdala of females with major depression. Depress Anxiety. 2017 Jan;34(1):68-78. PubMed PMID: 27557481; PubMed Central PMCID: PMC5222785.

Seney ML, Tripp A, McCune S, Lewis DA, Sibille E. Laminar and cellular analyses of reduced somatostatin gene expression in the subgenual anterior cingulate cortex in major depression. Neurobiol Dis. 2015 Jan;73:213-9. PubMed PMID: 25315685; PubMed Central PMCID: PMC4394026.

Seney ML, Chang LC, Oh H, Wang X, Tseng GC, Lewis DA, Sibille E. The Role of Genetic Sex in Affect Regulation and Expression of GABA-Related Genes Across Species. Front Psychiatry. 2013;4:104. PubMed PMID: 24062698; PubMed Central PMCID: PMC3775314.

Bassi S, Seney ML, Argibay P, Sibille E. Elevated Hippocampal Cholinergic Stimulating Peptide precursor protein (HCNP-PP) mRNA in the amygdala in major depression. J Psychiatr Res. 2015 63: 105-116. PMID: 25819500.

Golgi stained neuron

Mouse brain sections

Molecular rhythm alterations in psychiatric disorders and addiction

Abnormal circadian rhythms are a prominent and pervasive endophenotype of several psychiatric, neurological, and addiction disorders. However, very little is known about how circadian rhythms are disrupted at the molecular level in the brains of these patients.

Our laboratory uses novel biostatistical methods to examine of molecular rhythms in the human postmortem brain, and importantly, allows us to ask whether rhythm abnormalities exist in subjects with brain disorders. The laboratory also uses mouse models to examine whether disruption of brain molecular rhythms cause brain disorder-relevant phenotypes.

This knowledge has the potential to open novel treatment avenues via pharmacological targeting of these molecular rhythms.

Related publications:

Puig S, Shelton MA, Barko K, Seney ML, Logan RW. Sex-specific role of the circadian transcription factor NPAS2 in opioid tolerance, withdrawal and analgesia. 2022. Sep; 21(7):e12829. PMID: 36053258.

Xue X, Zong W, Glausier JR, Kim SM, Shelton MA, Phan BN, Srinivasan C, Pfenning AR, Tseng GC, Lewis DA, Seney ML, Logan RW. Molecular rhythm alterations in prefrontal cortex and nucleus accumbens associated with opioid use disorder. Transl Psychiatry. 2022. Mar 26; 12(1): 123. PMID: 35347109.

Logan RW, Xue X, Ketchesin KD, Hoffman G, Roussos P, Tseng G, McClung CA, Seney ML. Sex differences in molecular rhythms in the human cortex. Biol Psychiatry. 2022; Jan 1;91(1):152-162. PMID: 33934884.

Ketchesin KD, Zong W, Hildebrand M, Seney ML, Cahill K, Scott MR, Shankar VG, Glausier J, Lewis DA, Tseng G, McClung CA. Diurnal rhythms across the human dorsal and ventral striatum. Proc Natl Acad Sci USA. 2021;118(2):e2016150118. PMID: 33372142.

Seney ML, Cahill K, Enwright III JF, Logan RW, Huo Z, Zong W, Tseng G, McClung CA. Diurnal rhythms in gene expression in the prefrontal cortex in schizophrenia. Nature Communications. 2019;10(1):3355. PMID: 31399567.