Serine racemase: a key player in neuron activity and in neuropathologies

AbstractPost-traumatic stress disorder (PTSD) is a prevalent condition affecting approximately 8% of the United States population and 20% of United States combat veterans. In addition to core symptoms of the disorder, up to 64% of individuals diagnosed with PTSD experience comorbid psychosis. Previous research has demonstrated a positive correlation between symptoms of psychosis and increases in dopamine transmission. We have recently demonstrated projections from the paraventricular nucleus of the thalamus (PVT) to the nucleus accumbens (NAc) can regulate dopamine neuron activity in the ventral tegmental area (VTA). Specifically, inactivation of the PVT leads to a reversal of aberrant dopamine system function and psychosis-like behavior. The PVT receives dense innervation from orexin containing neurons, therefore, targeting orexin receptors may be a novel approach to restore dopamine neuron activity and alleviate PTSD-associated psychosis. In this study, we induced stress-related pathophysiology in male Sprague Dawley rats using an inescapable foot-shock procedure. We observed a significant increase in VTA dopamine neuron population activity, deficits in sensorimotor gating, and hyperresponsivity to psychomotor stimulants. Administration of selective orexin 1 receptor (OX1R) and orexin 2 receptor (OX2R) antagonists (SB334867 and EMPA, respectively) or the FDA-approved, dual-orexin receptor antagonist, Suvorexant, were found to reverse stress-induced increases in dopamine neuron population activity. However, only Suvorexant and SB334867 were able to reverse deficits in behavioral corelates of psychosis. These results suggest that the orexin system may be a novel pharmacological target for the treatment of comorbid psychosis related to PTSD.

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Evidence accumulation relates to perceptual consciousness and monitoring

Nature Communications ◽

10.1038/s41467-021-23540-y ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Michael Pereira ◽

Pierre Megevand ◽

Mi Xue Tan ◽

Wenwen Chang ◽

Shuo Wang ◽

...

Keyword(s):

Posterior Parietal Cortex ◽

Detection Threshold ◽

Task Demands ◽

Neuron Activity ◽

Neural Responses ◽

Neuronal Responses ◽

Neural Basis ◽

Perceptual Consciousness ◽

Evidence Accumulation ◽

Posterior Parietal

AbstractA fundamental scientific question concerns the neural basis of perceptual consciousness and perceptual monitoring resulting from the processing of sensory events. Although recent studies identified neurons reflecting stimulus visibility, their functional role remains unknown. Here, we show that perceptual consciousness and monitoring involve evidence accumulation. We recorded single-neuron activity in a participant with a microelectrode in the posterior parietal cortex, while they detected vibrotactile stimuli around detection threshold and provided confidence estimates. We find that detected stimuli elicited neuronal responses resembling evidence accumulation during decision-making, irrespective of motor confounds or task demands. We generalize these findings in healthy volunteers using electroencephalography. Behavioral and neural responses are reproduced with a computational model considering a stimulus as detected if accumulated evidence reaches a bound, and confidence as the distance between maximal evidence and that bound. We conclude that gradual changes in neuronal dynamics during evidence accumulation relates to perceptual consciousness and perceptual monitoring in humans.

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Changes in Prefrontal Cortex–Thalamic Circuitry after Acoustic Trauma

Biomedicines ◽

10.3390/biomedicines9010077 ◽

2021 ◽

Vol 9 (1) ◽

pp. 77

Author(s):

Kristin M. Barry ◽

Donald Robertson ◽

Wilhelmina H. A. M. Mulders

Keyword(s):

Electrical Stimulation ◽

Prefrontal Cortex ◽

Auditory System ◽

Acoustic Trauma ◽

Neuron Activity ◽

Compensatory Mechanism ◽

Efferent Connections ◽

Medial Geniculate ◽

Central Auditory Pathways ◽

Stimulation Of

In the adult auditory system, loss of input resulting from peripheral deafferentation is well known to lead to plasticity in the central nervous system, manifested as reorganization of cortical maps and altered activity throughout the central auditory pathways. The auditory system also has strong afferent and efferent connections with cortico-limbic circuitry including the prefrontal cortex and the question arises whether this circuitry is also affected by loss of peripheral input. Recent studies in our laboratory showed that PFC activation can modulate activity of the auditory thalamus or medial geniculate nucleus (MGN) in normal hearing rats. In addition, we have shown in rats that cochlear trauma resulted in altered spontaneous burst firing in MGN. However, whether the PFC influence on MGN is changed after cochlear trauma is unknown. We investigated the effects of electrical stimulation of PFC on single neuron activity in the MGN in anaesthetized Wistar rats 2 weeks after acoustic trauma or sham surgery. Electrical stimulation of PFC showed a variety of effects in MGN neurons both in sham and acoustic trauma groups but inhibitory responses were significantly larger in the acoustic trauma animals. These results suggest an alteration in functional connectivity between PFC and MGN after cochlear trauma. This change may be a compensatory mechanism increasing sensory gating after the development of altered spontaneous activity in MGN, to prevent altered activity reaching the cortex and conscious perception.

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The co-chaperone Fkbp5 shapes the acute stress response in the paraventricular nucleus of the hypothalamus of male mice

Molecular Psychiatry ◽

10.1038/s41380-021-01044-x ◽

2021 ◽

Author(s):

Alexander S. Häusl ◽

Lea M. Brix ◽

Jakob Hartmann ◽

Max L. Pöhlmann ◽

Juan-Pablo Lopez ◽

...

Keyword(s):

Stress Response ◽

Hpa Axis ◽

Paraventricular Nucleus ◽

Acute Stress ◽

Negative Regulator ◽

Neuron Activity ◽

Cell Type ◽

Specific Expression ◽

Acute Stress Response ◽

Cell Type Specific

AbstractDisturbed activation or regulation of the stress response through the hypothalamic-pituitary-adrenal (HPA) axis is a fundamental component of multiple stress-related diseases, including psychiatric, metabolic, and immune disorders. The FK506 binding protein 51 (FKBP5) is a negative regulator of the glucocorticoid receptor (GR), the main driver of HPA axis regulation, and FKBP5 polymorphisms have been repeatedly linked to stress-related disorders in humans. However, the specific role of Fkbp5 in the paraventricular nucleus of the hypothalamus (PVN) in shaping HPA axis (re)activity remains to be elucidated. We here demonstrate that the deletion of Fkbp5 in Sim1+ neurons dampens the acute stress response and increases GR sensitivity. In contrast, Fkbp5 overexpression in the PVN results in a chronic HPA axis over-activation, and a PVN-specific rescue of Fkbp5 expression in full Fkbp5 KO mice normalizes the HPA axis phenotype. Single-cell RNA sequencing revealed the cell-type-specific expression pattern of Fkbp5 in the PVN and showed that Fkbp5 expression is specifically upregulated in Crh+ neurons after stress. Finally, Crh-specific Fkbp5 overexpression alters Crh neuron activity, but only partially recapitulates the PVN-specific Fkbp5 overexpression phenotype. Together, the data establish the central and cell-type-specific importance of Fkbp5 in the PVN in shaping HPA axis regulation and the acute stress response.

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