Optogenetic stimulation of serotonin nuclei retrieve the lost memory in Alzheimer's disease

Abstract

How are memories stored and retrieved? It was one of the most discussed questions in the past century by neuroscientists. Leading studies of the period brought two different explanations to this question: The first statement considers memory as a physiological change in the brain and suggest that the retrieval of memory is only occurred by the same physiologic changes observed during the memory formation, while the second suggests that memory is a psychic mood stored in mind and the retrieval of memory is occurred by mystical energy fluctuations. Although the exact reason and the pathogenesis of Alzheimer's disease have not yet been fully understood, the approaches that centered the retrieval strategy of lost memory constitutes the basis of the treatment strategies in Alzheimer's disease today. The majority of treatment studies has based on the manipulation of the cholinergic system; however, although serotonin has mnemonic effects, its role in the pathogenesis of Alzheimer's disease has not been investigated as much as the cholinergic system. Here we show how serotonin affects the pathogenesis of Alzheimer's disease in a comprehensive perspective and we suggest that the optogenetics manipulation of serotonin nuclei retrieve the lost memory by closing the inward-rectifier potassium channel Kir2 on the memory engram cells. Also, we raise the possible effects of serotonin on the memory engram cells and the interactions between the amyloid-centric hypothesis of Alzheimer's disease and the memory engram hypothesis to explain the pathophysiology of memory loss in Alzheimer's disease.

Three-Week Treadmill Exercise Enhances Persistent Inward Currents, Facilitates Dendritic Plasticity, and Upregulates the Excitability of Dorsal Raphe Serotonin Neurons in ePet-EYFP Mice

“…Optogenetic (Warden et al, 2012 ) or pharmacogenetic (Teissier et al, 2015 ) activation of serotonin neurons in the DRN leads to antidepressant consequences, which is consistent with the effect of acute selective serotonin reuptake inhibitor (SSRI) administration (Kurt et al, 2000 ). In addition to mental disorder, dysfunction of the serotonergic system is also closely related to Alzheimer’s disease (Bostanciklioğlu, 2020 ) and Parkinson’s disease (Fox et al, 2009 ; Polotis and Niccolini, 2015 ). Although drugs that target 5-HT receptors and/or 5-HT transporter work well against the above diseases, side effects such as drug resistance and high recurrence rate are also reported in some studies (Mueller et al, 1999 ).…”

An update on memory formation and retrieval: An engram‐centric approach

“…We could speculate that the reason for increased serotonin level is to stimulate the release of neurotrophic factors triggering neuroplasticity and repairing mechanisms to protect neurons near to death, a destroying and exhausting process. A bulk of evidence indicated that serotonin is a key neuroprotective neurotransmitter 4 and this protective effect is specific for serotonin because other neurotransmitters trigger neuronal death process 99 …”

“…Close interactions between serotonin projections and memory engram cells. I created this figure for my last manuscript 4 . Here, I revised it by excluding the optogenetic tools on the figure and adding memory engram nuclei of prefrontal cortex (PFC), olfactory bulbus (OB), and nucleus accumbens (NAcc) to emphasize how serotonin fluctuations can easily affect the excitability state of memory engram neurons.…”

Unexpected awakenings in severe dementia from case reports to laboratory

“…106 Because tryptophan is a key amino acid for serotonin production, this model is characterized by decreased serotonin production. At this stage, an instantaneous increase of serotonin level by an artificial stimulation, such as optogenetic 107 in other words, the hippocampus retains only the entry circuit of the memory, not the complete information.…”

“…Because tryptophan is a key amino acid for serotonin production, this model is characterized by decreased serotonin production. At this stage, an instantaneous increase of serotonin level by an artificial stimulation, such as optogenetic 107 or pharmacologic, or increase of neural excitability apart from serotonin by a mediator heavily implicated to be increased in elders, such as CRF, can produce an instantaneous episode of lucidity. It was clear that a striking increase in serotonin levels is observed near death when lucid episodes have been commonly documented.…”