Activation of Dopamine D2 Receptors Alleviates Neuronal Hyperexcitability in the Lateral Entorhinal Cortex via Inhibition of HCN Current in a Rat Model of Chronic Inflammatory Pain

Functional changes in synaptic transmission from the lateral entorhinal cortex to the dentate gyrus(LEC-DG)are considered responsible for the chronification of pain.However,the underlying alterations in fan cells,which are the predominant neurons in the LEC that project to the DG,remain elusive.Here,we investigated possible mechanisms using a rat model of complete Freund’s adjuvant(CFA)-induced inflammatory pain.We found a substantial increase in hyperpolarization-activated/cyclic nucleotide-gated currents(Ih),which led to the hyperexcitability of LEC fan cells of CFA slices.This phenomenon was attenuated in CFA slices by activating dopamine D2,but not D1,receptors.Chemogenetic activation of the ventral tegmental area-LEC projection had a D2 receptor-dependent analgesic effect.Intra-LEC microinjection of a D2 receptor agonist also suppressed CFA-induced behavioral hypersensitivity,and this effect was attenuated by pre-activation of the Ih.Our findings suggest that down-regulating the excitability of LEC fan cells through activation of the dopamine D2 receptor may be a strategy for treating chronic inflammatory pain.

Impaired Parahippocampal Gyrus-Orbitofrontal Cortex Circuit Associated with Visuospatial Memory Deficit as a Potential Biomarker and Interventional Approach for Alzheimer Disease

The parahippocampal gyrus-orbitofrontal cortex(PHG-OFC)circuit in humans is homologous to the postrhinal cortex(POR)-ventral lateral orbitofrontal cortex(vlOFC)circuit in rodents.Both are associated with visuospatial malfunctions in Alzheimer’s disease(AD).However,the underlying mechanisms remain to be elucidated.In this study,we explored the relationship between an impaired POR-vlOFC circuit and visuospatial memory deficits through retrograde tracing and in vivo local field potential recordings in 5XFAD mice,and investigated alterations of the PHG-OFC circuit by multi-domain magnetic resonance imaging(MRI)in patients on the AD spectrum.We demonstrated that an impaired glutamatergic POR-vlOFC circuit resulted in deficient visuospatial memory in 5XFAD mice.Moreover,MRI measurements of the PHG-OFC circuit had an accuracy of 77.33%for the classification of amnestic mild cognitive impairment converters versus non-converters.Thus,the PHG-OFC circuit explains the neuroanatomical basis of visuospatial memory deficits in AD,thereby providing a potential predictor for AD progression and a promising interventional approach for AD.

Neuronal Response to Reward and Luminance in Macaque LIP During Saccadic Choice

Recent work in decision neuroscience suggests that visual saliency can interact with reward-based choice,and the lateral intraparietal cortex(LIP)is implicated in this process.In this study,we recorded from LIP neurons while monkeys performed a two alternative choice task in which the reward and luminance associated with each offer were varied independently.We discovered that the animal’s choice was dictated by the reward amount while the luminance had a marginal effect.In the LIP,neuronal activity corresponded well with the animal’s choice pattern,in that a majority of reward-modulated neurons encoded the reward amount in the neuron’s preferred hemifield with a positive slope.In contrast,compared to their responses to low luminance,an approximately equal proportion of luminance-sensitive neurons responded to high luminance with increased or decreased activity,leading to a much weaker population-level response.Meanwhile,in the non-preferred hemifield,the strength of encoding for reward amount and luminance was positively correlated,suggesting the integration of these two factors in the LIP.Moreover,neurons encoding reward and luminance were homogeneously distributed along the anterior-posterior axis of the LIP.Overall,our study provides further evidence supporting the neural instantiation of a priority map in the LIP in reward-based decisions.