Psilocybin exerts distinct effects on resting state networks associated with serotonin and dopamine in mice.

Hallucinogenic agents have been proposed as potent antidepressants; this includes the serotonin (5-HT) receptor 2A agonist psilocybin. In human subjects, psilocybin alters functional connectivity (FC) within the default-mode network (DMN), a constellation of inter-connected regions that displays altered FC in depressive disorders. In this study, we investigated the effects of psilocybin on FC across the entire brain with a view to investigate underlying mechanisms. Psilocybin effects were investigated in lightly-anaesthetized mice using resting-state fMRI. Dual-regression analysis identified reduced FC within the ventral striatum in psilocybin- relative to vehicle-treated mice. Refinement of the analysis using spatial references derived from both gene expression maps and viral tracer projection fields revealed two distinct effects of psilocybin: it increased FC between 5-HT-associated networks and cortical areas, including elements of the murine DMN, thalamus, and midbrain; it decreased FC within dopamine (DA)-associated striatal networks. These results suggest that interactions between 5-HT- and DA-regulated neural networks contribute to the neural and therefore psychological effects of psilocybin. Furthermore, they highlight how information on molecular expression patterns and structural connectivity can assist in the interpretation of pharmaco-fMRI findings.

Dynamic reorganization of intrinsic functional networks in the mouse brain.

Functional connectivity (FC) derived from resting-state functional magnetic resonance imaging (rs-fMRI) allows for the integrative study of neuronal processes at a macroscopic level. The majority of studies to date have assumed stationary interactions between brain regions, without considering the dynamic aspects of network organization. Only recently has the latter received increased attention, predominantly in human studies. Applying dynamic FC (dFC) analysis to mice is attractive given the relative simplicity of the mouse brain and the possibility to explore mechanisms underlying network dynamics using pharmacological, environmental or genetic interventions. Therefore, we have evaluated the feasibility and research potential of mouse dFC using the interventions of social stress or anesthesia duration as two case-study examples. By combining a sliding-window correlation approach with dictionary learning, several dynamic functional states (dFS) with a complex organization were identified, exhibiting highly dynamic inter- and intra-modular interactions. Each dFS displayed a high degree of reproducibility upon changes in analytical parameters and across datasets. They fluctuated at different degrees as a function of anesthetic depth, and were sensitive indicators of pathology as shown for the chronic psychosocial stress mouse model of depression. Dynamic functional states are proposed to make a major contribution to information integration and processing in the healthy and diseased brain.

Region- and receptor-specific effects of chronic social stress on the central serotonergic system in mice.

Serotonin (5-HT), via its receptors expressed in discrete brain regions, modulates aversion and reward processing and is implicated in various psychiatric disorders including depression. Stressful experiences affect central serotonergic activity and act as a risk factor for depression; this can be modelled preclinically. In adult male C57BL/6J mice, 15-day chronic social stress (CSS) leads to depression-relevant behavioural states, including increased aversion and reduced reward sensitivity. Based on this evidence, here we investigated CSS effects on 5-HT1A, 5-HT2A, and 5-HT2C receptor binding in discrete brain regions using in vitro quantitative autoradiography with selective radioligands. In addition, mRNA expression of Htr1a, 2a, 2c and Slc6a4 (5-HT transporter) was measured by quantitative PCR. Relative to controls, the following effects were observed in CSS mice: 5-HT1A receptor binding was markedly increased in the dorsal raphe nucleus (136%); Htr1a mRNA expression was increased in raphe nuclei (19%), medial prefrontal cortex (35%), and hypothalamic para- and periventricular nuclei (21%) and ventral medial nucleus (38%). 5-HT2A receptor binding was decreased in the amygdala (48%) and ventral tegmental area (60%); Htr2a mRNA expression was increased in the baso-lateral amygdala (116%). 5-HT2C receptor binding was decreased in the dorsal raphe nucleus (42%). Slc6a4 mRNA expression was increased in the raphe (59%). The present findings add to the translational evidence that chronic social stress impacts on the central serotonergic system in a region- and receptor-specific manner, and that this altered state of the serotonergic system contributes to stress-induced dysfunctions in emotional processing.

Chronic social stress induces peripheral and central immune activation, blunted mesolimbic dopamine function, and reduced reward-directed behaviour in mice.

Psychosocial stress is a major risk factor for depression, stress leads to peripheral and central immune activation, immune activation is associated with blunted dopamine (DA) neural function, DA function underlies reward interest, and reduced reward interest is a core symptom of depression. These states might be inter-independent in a complex causal pathway. Whilst animal-model evidence exists for some specific steps in the pathway, there is currently no animal model in which it has been demonstrated that social stress leads to each of these immune, neural and behavioural states. Such a model would provide important existential evidence for the complex pathway and would enable the study of causality and mediating mechanisms at specific steps in the pathway. Therefore, in the present mouse study we investigated for effects of 15-day resident-intruder chronic social stress (CSS) on each of these states. Relative to controls, CSS mice exhibited higher spleen levels of granulocytes, inflammatory monocytes and T helper 17 cells; plasma levels of inducible nitric oxide synthase; and liver expression of genes encoding kynurenine pathway enzymes. CSS led in the ventral tegmental area to higher levels of kynurenine and the microglia markers Iba1 and Cd11b and higher binding activity of DA D1 receptor; and in the nucleus accumbens (NAcc) to higher kynurenine, lower DA turnover and lower c-fos expression. Pharmacological challenge with DA reuptake inhibitor identified attenuation of DA stimulatory effects on locomotor activity and NAcc c-fos expression in CSS mice. In behavioural tests of operant responding for sucrose reward validated as sensitive assays for NAcc DA function, CSS mice exhibited less reward-directed behaviour. Therefore, this mouse study demonstrates that a chronic social stressor leads to changes in each of the immune, neural and behavioural states proposed to mediate between stress and disruption of DA-dependent reward processing. The model can now be applied to investigate causality and, if demonstrated, underlying mechanisms in specific steps of this immune-neural-behavioural pathway, and thereby to identify potential therapeutic targets.