Hidalgo, J. | Search bioRxiv

bioRxiv2022

Differential role of dopamine D3 receptor through balanced modulation of Akt/mTOR and ERK1/2 activity in the reactivation of cocaine rewarding memories evoked by psychological versus physiological stress

Stress is an important trigger of relapses in cocaine use. These relapses engage the activity of memory-related nuclei, such as the basolateral amygdala (BLA) and the dentate gyrus (DG). Further, preclinical research signals D3 receptor (D3R) antagonists as promising therapeutic tools to attenuate cocaine reward and relapse. Therefore, we assessed the effect of SB-277011-A, a D3R antagonist, in the activity of Akt/mTOR and MEK/ERK1/2 pathways in these areas during the reinstatement of cocaine-induced conditioned place preference (CPP) evoked by psychological (restraint) and physiological (tail pinch) stress. Both stimuli reactivated the extinguished cocaine-CPP, but only restrained animals decreased their locomotor activity during reinstatement. Moreover, p-Akt, p-mTOR and p-ERK1/2 activity in the BLA and DG of restrained animals decreased during the reactivation of cocaine memories, contrasting to tail-pinched mice. While D3R blockade prevented stress-induced CPP reactivation and plasmatic corticosterone enhancement, SB-277011-A distinctly modulated Akt, mTOR and ERK1/2 activities in the BLA and DG based on the stressor and the dose of antagonist. Corticosterone may be partially responsible for these variations as we found high correlations among its levels and mTOR and/or Akt activity in the BLA and DG of restrained animals receiving SB-277011-A. Besides, locomotor activity of animals receiving 48 mg/kg of the antagonist highly correlated with p-mTOR/mTOR and p-ERK1/2 /ERK1/2 in the BLA during restraint- and tail pinch-induced relapse in cocaine-CPP, respectively. Hence, our study endorses D3R antagonists as therapeutic tools to prevent stress-induced relapses in drug use through a complex balance of Akt/mTOR and MEK/ERK1/2 pathways in memory-processing brain nuclei.

neuroscience↗

bioRxiv2020

Robust Cortical Criticality and Diverse Neural Network Dynamics Resulting from Functional Specification

Despite recognized layered structure and increasing evidence for criticality in the cortex, how the specification of input, output and computational layers affects the self-organized criticality has been surprisingly neglected. By constructing heterogeneous structures with a well-accepted model of leaky neurons, we found that the specification can lead to robust criticality almost insensitive to the strength of external stimuli. This naturally unifies the adaptation to strong inputs without extra synaptic plasticity mechanisms. Presence of output neurons constitutes an alternative explanation to subcriticality other than the high frequency inputs. Degree of recurrence is proposed as a network metric to account for the signal termination due to output neurons. Unlike fully recurrent networks where external stimuli always render subcriticality, the dynamics of networks with sufficient feed-forward connections can be driven to criticality and supercriticality. These findings indicate that functional and structural specification and their interplay with external stimuli are of crucial importance for the network dynamics. The robust criticality puts forward networks of the leaky neurons as a promising platform for realizing artificial neural networks that work in the vicinity of critical points.

neuroscience↗