Decreased Numbers of Somatostatin-Expressing Neurons in the Amygdala of Subjects With Bipolar Disorder or Schizophrenia: Relationship to Circadian Rhythms

Abstract

Background Growing evidence points to a key role for somatostatin (SST) in schizophrenia (SZ) and bipolar disorder (BD). In the amygdala, neurons expressing SST play an important role in the regulation of anxiety, often comorbid in these disorders. We tested the hypothesis that SST-immunoreactive (IR) neurons are decreased in the amygdala of subjects with SZ and BD. Evidence for circadian SST expression in the amygdala and disrupted circadian rhythms and rhythmic peaks of anxiety in BD suggest a disruption of rhythmic expression of SST in this disorder. Methods Amygdala sections from 12 SZ, 15 BD, and 15 control subjects were processed for immunocytochemistry for SST and neuropeptide Y (NPY), a neuropeptide partially co-expressed in SST-IR neurons. Total numbers (Nt) of IR neurons were measured. Time of death (TOD) was used to test associations with circadian rhythms. Results SST-IR neurons were decreased in the lateral amygdala nucleus in BD (Nt, p= 0.003) and SZ (Nt, p=0.02). In normal controls, Nt of SST-IR neurons varied according to TOD. This pattern was altered in BD, characterized by decreases of SST-IR neurons selectively in subjects with TOD corresponding to the day (06:00–17:59). Numbers of NPY-IR neurons were not affected. Conclusions Decreased SST-IR neurons in the amygdala of SZ and BD, interpreted here as decreased SST expression, may disrupt responses to fear and anxiety regulation in these subjects. In BD, our findings raise the possibility that morning peaks of anxiety depend on a disruption of circadian regulation of SST expression in the amygdala.

Circadian Rhythms of Perineuronal Net Composition

“…Effects of TOD on outcome measures were analyzed using two steps: 1) Subjects were divided into s-Day vs. s-Night groups for comparisons using stepwise linear regression analysis 2) We used quartic regression analysis on plots of Nt of WFA labeled PNNs by TOD for each group according to methods used to detect similar relationships in postmortem studies (Zhou et al, 2001;Hofman, 2003;Li et al, 2013). Quartic regression models were used as described previously to fit expression patterns reported in the mouse and human amygdala consisting of two peaks and two troughs (Albrecht et al, 2013;Pantazopoulos et al, 2017).…”

“…Consistent with these observations, PNNs have been implicated in several brain disorders involving these regions, including schizophrenia, bipolar disorder, Alzheimer's disease and addiction (Baig et al, 2005;Morawski et al, 2010;Pantazopoulos et al, 2010a;Mauney et al, 2013;Xue et al, 2014;Pantazopoulos et al, 2015;Slaker et al, 2015;Steullet et al, 2017;Blacktop and Sorg, 2018). Several of these disorders also show altered sleep and circadian rhythms (Lim et al, 2013;McClung, 2013;Wang et al, 2015;Manoach et al, 2016;Pantazopoulos et al, 2017). Thus, diurnal modulation of PNNs has a broad range of implications for psychiatric disorders and memory processing.…”

“…We tested the hypothesis that PNNs vary in a circadian manner, and that cathepsin-S contributes to this regulation. In mice, we first assessed densities of PNNs across the 24-hour cycle in brain regions involved in emotional memory processing and implicated in psychiatric disorders (Vyas et al, 2002;Sartorius et al, 2010;Li et al, 2011;Mahan and Ressler, 2012;Mauney et al, 2013;Meyer et al, 2014;Pantazopoulos et al, 2017;Wells et al, 2017). We then assessed the relationship between PNNs and sleep by testing the effect of sleep deprivation on PNN densities in the hippocampus, a brain region in which diurnal differences in LTP were reported (Chaudhury et al, 2005).…”

Effect of long-term treatment with classical neuroleptics on NPQ/spexin, kisspeptin and POMC mRNA expression in the male rat amygdala

“…The recent study seems to supports this hypothesis showing that in patients with schizophrenia spectrum disorders (SCZ) the oxytocin receptor gene polymorphisms were associated with low amygdala activation (Haram et al 2016). Furthermore, the number of somatostatin-expressing neurons was decreased in the amygdala of patients with schizophrenia (Pantazopoulos et al 2017). On the other hand, an interesting study by Majercikova and Kiss (2015) shed surprising light on the matter of antipsychotic action at the level of peptidergic pathways in the rat amygdala.…”

Forced Abstinence from Alcohol Induces Sex-Specific Depression-like Behavioral and Neural Adaptations in Somatostatin Neurons in Cortical and Amygdalar Regions

“…In the cortex, SST neurons are often postulated to be the gatekeeper of thalamo-and cortico-cortical excitatory inputs to pyramidal neurons, via their soma-and dendrite-targeting synapses (Urban-Ciecko & Barth, 2016). These neurons recently gained substantial interest for their role in a host of neuropsychiatric disorders, including MDD, bipolar disorder, schizophrenia (Abbas et al, 2018;Fee et al, 2017;Pantazopoulos et al, 2017).…”