Optogenetic inhibition of ventral hippocampal neurons alleviates associative motor learning dysfunction in a rodent model of schizophrenia

Abstract

Schizophrenia (SZ) is a serious and incurable mental disorder characterized by clinical manifestations of positive and negative symptoms and cognitive dysfunction. High-frequency deep brain stimulation (DBS) of the ventral hippocampus (VHP) has been recently applied as a therapeutic approach for SZ in both experimental and clinical studies. However, little is known about the precise mechanism of VHP-DBS treatment for SZ and the role of hippocampal cell activation in the pathogenesis of SZ. With optogenetic technology in this study, we tried to inhibit neuronal activity in the VHP which has dense projections to the prefrontal cortex, before measuring long stumulus-induced delay eyeblink conditioning (long-dEBC) in a rodent model of SZ. Rats were administrated with phencyclidine (PCP, 3 mg/kg, 1/d, ip) for successive 7 days before optogenetic intervention. The current data show that PCP administration causes significant impairment in the acquisition and timing of long-dEBC; the inhibition of bilateral VHP neurons alleviates the decreased acquisition and impaired timing of longd-dEBC in PCP-administered rats. The results provide direct evidence at the cellular level that the inhibition of VHP neuronal cells may be a prominent effect of hippocampal DBS intervention, and increased activity in the hippocampal network play a pivotal role in SZ.

Fine mapping of the major QTLs for biochemical variation of sulforaphane in broccoli florets using a DH population

“…It has been reported that this conclusion is also applicable the GRA and SF in broccoli. Moreover, different organs of broccoli, including the seeds, seedlings, sprouts, leaves, and stalks, present quite different SF contents, which are mostly determined by the genotype and its interactions with the environment 22 , 40 – 44 . Similarly, in the florets and leaves that we analyzed, it was shown that there were significant variations in SF accumulation in different genotypes and organs at different developmental stages (florets at mature, buds to flowers at bolting) 3 , 22 .…”

“… 21 – 23 . GLS show great differences among different organs 20 , 22 , 24 . Therefore, the glucosinolate content depends not only on the genotype but also on the growing environment 2 , 25 .…”

The Memory-Modifying Potential of Optogenetics and the Need for Neuroethics

“…Another disease awaiting the approval of initial clinical trials involving the application of optogenetic therapy and for which existing methods of treatment show limited effectiveness is urinary bladder syndrome [5]. Furthermore, many optogenetic studies conducted on animal models, such as rodents or nonhuman primates [6], were designed with the explicit goal of developing better targeted brain stimulation treatments for various psychiatric and neurological disorders in humans [7][8][9][10][11][12][13][14]. These attempts, along with rapid advancements in the field, demonstrate that optogenetics is already progressing towards clinical application.…”

“…Furthermore, to stimulate a targeted brain region efficiently, an implantable optogenetic device requires a sufficient light spread and intensity range and must be able to generate diverse illumination patterns (e.g., continuous illumination or short light pulses of changeable frequencies) and wavelengths suitable for activation of the targeted photosensory proteins of interest. 10 Until recently, neuronal illumination and recording of a neuron's evoked electrical signal required the insertion of two relatively large devices into the brain: fiber optic probes and so-called "optrodes" (fiber optics combined with electrodes). This procedure was highly invasive and characterized by increased tissue damage and declining optical output over time.…”

“…Some of the most basic ethical issues (such as efficacy and safety concerns) associated with the application of optogenetics to humans have already begun to be addressed [21][22][23][24][25]. However, as optogenetics is being intensively investigated in the context of the development of effective brain stimulation treatments for various neurological and psychiatric disorders such as depression [8], schizophrenia [10,13], anxiety and pain [11], movement disorders [14], including Parkinson's disease [9,65], addictions [90], epilepsy [91], and memory-related disorders such as PTSD [12], diencephalic amnesia, and Alzheimer's disease [7], it is conceivable that optogenetics or other optogenetic-like neurostimulation methods (that allow for a similar degree of neural specificity and precision, will eventually be used to apply these findings as a form of therapy in humans. And, indeed, some optogenetics findings regarding characterization of neural circuits and their dysfunction in various brain diseases are currently inspiring novel stimulation protocols that are planned to be applied as a form of treatment in humans by means of refined DBS [92].…”