Perhaps the most important question posed by brain research is: How the brain gives rise to the mind. To answer this question, we have primarily relied on the connectionist paradigm: The brain's entire knowledge and thinking skills are thought to be stored in the connections; and the mental operations are executed by network computations. I propose here an alternative paradigm: Our knowledge and skills are stored in metabotropic receptors (MRs) and the G protein-gated ion channels (GPGICs). Here, mental operations are assumed to be executed by the functions of MRs and GPGICs. As GPGICs have the capacity to close or open branches of dendritic trees and axon terminals, their states transiently re-route neural activity throughout the nervous system. First, MRs detect ligands that signal the need to activate GPGICs. Next, GPGICs transiently select a subnetwork within the brain. The process of selecting this new subnetwork is what constitutes a mental operation - be it in a form of directed attention, perception or making a decision. Synaptic connections and network computations play only a secondary role, supporting MRs and GPGICs. According to this new paradigm, the mind emerges within the brain as the function of MRs and GPGICs whose primary function is to continually select the pathways over which neural activity will be allowed to pass. It is argued that MRs and GPGICs solve the scaling problem of intelligence from which the connectionism paradigm suffers.
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http://dx.doi.org/10.1016/j.compbiolchem.2023.107820 | DOI Listing |
Pharmacol Ther
December 2024
Fang Zongxi Center for Marine EvoDevo, MoE Key Laboratory of Marine Genetics and Breeding, College of Marine Life Sciences, Ocean University of China, Qingdao 266003, China; Insititute of Evolution & Marine Biodiversity, Ocean University of China, Qingdao 266003, China.. Electronic address:
G protein-coupled receptors (GPCRs), the largest family of membrane receptors in the mammalian genomes, regulate almost all known physiological processes by transducing numerous extracellular stimuli including almost two-thirds of endogenous hormones and neurotransmitters. The traditional view held that GPCR signaling occurs exclusively at the cell surface, where the receptors bind with the ligands and undergo conformational changes to recruit and activate heterotrimeric G proteins. However, with the application of advanced biochemical and biophysical techniques, this conventional model is challenged by the elucidation of spatiotemporal GPCR activation with the evidence that receptors can signal from subcellular compartments to exhibit various molecular and cellular responses with physiological and pathophysiological relevance.
View Article and Find Full Text PDFCogn Neurodyn
December 2024
School of Mathematics and Statistics, Shaanxi Normal University, Xi'an, 710119 People's Republic of China.
The accumulation of amyloid peptide is assumed to be one of the main causes of Alzheimer's disease . There is increasing evidence that astrocytes are the primary targets of A. A can cause abnormal synaptic glutamate, aberrant extrasynaptic glutamate, and astrocytic calcium dysregulation through astrocyte glutamate transporters facing the synaptic cleft (GLT-syn), astrocyte glutamate transporters facing the extrasynaptic space (GLT-ess), metabotropic glutamate receptors in astrocytes (mGluR), N-methyl-D-aspartate receptors in astrocytes (NMDAR), and glutamatergic gliotransmitter release (Glio-Rel).
View Article and Find Full Text PDFJ Physiol
December 2024
Department of Cell Biology & Anatomy, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
In recent years, evidence supporting non-ionotropic signalling by the NMDA receptor (niNMDAR) has emerged, including roles in long-term depression (LTD). Here, we investigated whether niNMDAR-pannexin-1 (Panx1) contributes to LTD at the CA3-CA1 hippocampal synapse. Using whole-cell, patch clamp electrophysiology in rat hippocampal slices, we show that a low-frequency stimulation (3 Hz) of the Schaffer collaterals produces LTD that is blocked by continuous but not transient application of the NMDAR competitive antagonist, MK-801.
View Article and Find Full Text PDFACS Pharmacol Transl Sci
December 2024
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, VIC 3052, Australia.
Metabotropic glutamate receptors are a family of eight class C G protein-coupled receptors regulating higher order brain functions including cognition and motion. Metabotropic glutamate receptors have thus been heavily investigated as potential drug targets for treating neurological disorders. Drug discovery efforts directed toward metabotropic glutamate receptor subtype 5 (mGlu) have been particularly fruitful, with a wealth of drug candidates and pharmacological tools identified.
View Article and Find Full Text PDFJ Neurochem
January 2025
College of Pharmacy, Chonnam National University, Gwangju, Republic of Korea.
The α4β2 nicotinic acetylcholine receptor (nAChR), an ionophore, has been suggested to signal through metabotropic pathways and interact with other receptor families, such as dopamine receptors. In this study, the interaction between α4β2 nAChR and dopamine receptors was investigated through in vivo and in vitro studies. Nicotine exposure in adolescent rats is known to induce a sustained increase in nicotine's rewarding effects which was assessed by conditioned place preference (CPP) assay.
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