Neural mechanisms underlying psilocybin's therapeutic potential - the need for preclinical in vivo electrophysiology.

Psilocybin is a naturally occurring psychedelic compound with profound perception-, emotion- and cognition-altering properties and great potential for treating brain disorders. However, the neural mechanisms mediating its effects require in-depth investigation as there is still much to learn about how psychedelic drugs produce their profound and long-lasting effects. In this review, we outline the current understanding of the neurophysiology of psilocybin's psychoactive properties, highlighting the need for additional preclinical studies to determine its effect on neural network dynamics. We first describe how psilocybin's effect on brain regions associated with the default-mode network (DMN), particularly the prefrontal cortex and hippocampus, likely plays a key role in mediating its consciousness-altering properties. We then outline the specific receptor and cell types involved and discuss contradictory evidence from neuroimaging studies regarding psilocybin's net effect on activity within these regions. We go on to argue that in vivo electrophysiology is ideally suited to provide a more holistic, neural network analysis approach to understand psilocybin's mode of action. Thus, we integrate information about the neural bases for oscillatory activity generation with the accumulating evidence about psychedelic drug effects on neural synchrony within DMN-associated areas. This approach will help to generate important questions for future preclinical and clinical studies. Answers to these questions are vital for determining the neural mechanisms mediating psilocybin's psychotherapeutic potential, which promises to improve outcomes for patients with severe depression and other difficulty to treat conditions.

Functional ultrasound imaging of recent and remote memory recall in the associative fear neural network in mice.

Emotional learning and memory are affected in numerous psychiatric disorders. At a systems level, however, the underlying neural circuitry is not well defined. Rodent fear conditioning (FC) provides a translational model to study the networks underlying associative memory retrieval. In the current study, functional connectivity among regions related to the cue associative fear network were investigated using functional ultrasound (fUS), a novel imaging technique with great potential for detecting neural activity through cerebral blood flow. Behavioral fear expression and fUS imaging were performed one and thirty-one days after FC to assess recent and remote memory recall. Cue-evoked increases in functional connectivity were detected throughout the amygdala, with the lateral (LA) and central (CeA) amygdalar nuclei emerging as major hubs of connectivity, although CeA connectivity was reduced during remote recall. Hippocampal and sensory cortical regions displayed heightened connectivity with the LA during remote recall, whereas interconnectivity between the primary auditory cortex and temporal association areas was reduced. Subregions of the prefrontal cortex exhibited variable changes, where prelimbic connectivity with the amygdala was refined while specific connections between the infralimbic cortex and amygdalar subregions emerged during remote memory retrieval, a signature of extinction memory. Moreover, freezing behavior positively correlated with functional connectivity between hubs of the associative fear network, suggesting that emotional response intensity reflected the strength of the cue-evoked functional network. Overall, our data provide evidence of the functionality of fUS imaging to investigate the neural dynamics of memory retrieval, applicable in the development of innovative treatments for affective disorders.

Synaptic biomarker reduction and impaired cognition in the sub-chronic PCP mouse model for schizophrenia.

BACKGROUND: Sub-chronic phencyclidine treatment (scPCP) provides a translational rat model for cognitive impairments associated with schizophrenia (CIAS). CIAS genetic risk factors may be more easily studied in mice; however, CIAS associated biomarker changes are relatively unstudied in the scPCP mouse. AIM: To characterize deficits in object recognition memory and synaptic markers in frontal cortex and hippocampus of the scPCP mouse. METHODS: Female c57/bl6 mice received 10 daily injections of PCP (scPCP; 10 mg/kg, s.c.) or vehicle (n = 8/group). Mice were tested for novel object recognition memory after either remaining in the arena ('no distraction') or being removed to a holding cage ('distraction') during the inter-trial interval. Expression changes for parvalbumin (PV), glutamic acid decarboxylase (GAD67), synaptosomal-associated protein 25 (SNAP-25) and postsynaptic density 95 (PDS95) were measured in frontal cortex, dorsal and ventral hippocampus. RESULTS: scPCP mice showed object memory deficits when distracted by removal from the arena, where they treated previously experienced objects as novel at test. scPCP significantly reduced PV expression in all regions and lower PSD95 levels in frontal cortex and ventral hippocampus. Levels of GAD67 and SNAP-25 were unchanged. CONCLUSIONS: We show for the first time that scPCP mice: (a) can encode and retain object information, but that this memory is susceptible to distraction; (b) display amnesia after distraction; and (c) express reduced PV and PSD95 in frontal cortex and hippocampus. These data further support reductions in PV-dependent synaptic inhibition and NMDAR-dependent glutamatergic plasticity in CIAS and highlight the translational significance of the scPCP mouse.