Representational ‘touch’ and modulatory ‘retouch’—two necessary neurobiological processes in thalamocortical interaction for conscious experience

Theories of consciousness using neurobiological data or being influenced by these data have been focused either on states of consciousness or contents of consciousness. These theories have occasionally used evidence from psychophysical phenomena where conscious experience is a dependent experimental variable. However, systematic catalog of many such relevant phenomena has not been offered in terms of these theories. In the perceptual retouch theory of thalamocortical interaction, recently developed to become a blend with the dendritic integration theory, consciousness states and contents of consciousness are explained by the same mechanism. This general-purpose mechanism has modulation of the cortical layer-5 pyramidal neurons that represent contents of consciousness as its core. As a surplus, many experimental psychophysical phenomena of conscious perception can be explained by the workings of this mechanism. Historical origins and current views inherent in this theory are presented and reviewed.

An astrocytic signaling loop for frequency-dependent control of dendritic integration and spatial learning

Dendrites of hippocampal CA1 pyramidal cells amplify clustered glutamatergic input by activation of voltage-gated sodium channels and N-methyl-D-aspartate receptors (NMDARs). NMDAR activity depends on the presence of NMDAR co-agonists such as D-serine, but how co-agonists influence dendritic integration is not well understood. Using combinations of whole-cell patch clamp, iontophoretic glutamate application, two-photon excitation fluorescence microscopy and glutamate uncaging we found that exogenous D-serine reduces the threshold of dendritic spikes and increases their amplitude. Triggering an astrocytic mechanism controlling endogenous D-serine supply via endocannabinoid receptors (CBRs) also increased dendritic spiking. Unexpectedly, this pathway was activated by pyramidal cell activity primarily in the theta range, which required HCN channels and astrocytic CB1Rs. Therefore, astrocytes close a positive and frequency-dependent feedback loop between pyramidal cell activity and their integration of dendritic input. Its disruption led to an impairment of spatial memory, which demonstrates its behavioral relevance.

Asymptotic Input-Output Relationship Predicts Electric Field Effect on Sublinear Dendritic Integration of AMPA Synapses

An extracellular electric field (EF) induces transmembrane polarizations on extremely inhomogeneous spaces Evidence shows that EF-induced somatic polarization in pyramidal cells can modulate the neuronal input-output (I/O) function. However, it remains unclear whether and how dendritic polarization participates in the dendritic integration and contributes to the neuronal I/O function. To this end, we built a computational model of a simplified pyramidal cell with multi-dendritic tufts, one dendritic trunk, and one soma to describe the interactions among EF, dendritic integration, and somatic output, in which the EFs were modeled by inserting inhomogeneous extracellular potentials. We aimed to establish the underlying relationship between dendritic polarization and dendritic integration by analyzing the dynamics of subthreshold membrane potentials in response to AMPA synapses in the presence of constant EFs. The model-based singular perturbation analysis showed that the equilibrium mapping of a fast subsystem can serve as the asymptotic subthreshold I/O relationship for sublinear dendritic integration. This allows us to predict the tendency of EF-mediated dendritic integration by showing how EF changes modify equilibrium mapping. EF-induced hyperpolarization of distal dendrites receiving synapses inputs was found to play a key role in facilitating the AMPA receptor-evoked excitatory postsynaptic potential (EPSP) by enhancing the driving force of synaptic inputs. A significantly higher efficacy of EF modulation effect on global AMPA-type dendritic integration was found compared with local AMPA-type dendritic integration. During the generation of an action potential (AP), the relative contribution of EF-modulated dendritic integration and EF-induced somatic polarization was determined to show their collaboration in promoting or inhibiting the somatic excitability, depending on the EF polarity. These findings are crucial for understanding the EF modulation effect on neuronal computation, which provides insight into the modulation mechanism of noninvasive brain modulation.

Reduced expression of the psychiatric risk gene DLG2 (PSD93) impairs hippocampal synaptic integration and plasticity

Background: Genetic variations indicating loss of function in the DLG2 gene have been associated with markedly increased risk for schizophrenia, autism spectrum disorder, and intellectual disability. DLG2 encodes the postsynaptic scaffolding protein DLG2 (PSD93) that interacts with NMDA receptors, potassium channels, and cytoskeletal regulators but the net impact of these interactions on synaptic plasticity, likely underpinning cognitive impairments associated with these conditions, remains unclear. Methods: Hippocampal CA1 neuronal excitability and synaptic function were investigated in a novel clinically relevant heterozygous Dlg2+/- rat model using ex vivo patch-clamp electrophysiology, pharmacology, and computational modelling. Results: Dlg2+/- rats had increased NMDA receptor-mediated synaptic currents and, conversely, impaired associative long-term potentiation. This impairment resulted from an increase in potassium channel function leading to a decrease in input resistance and reduced supra-linear dendritic integration during induction of associative long-term potentiation. Enhancement of dendritic excitability by blockade of potassium channels or activation of muscarinic M1 receptors with selective allosteric agonist 77-LH-28- 1 reduced the threshold for dendritic integration and 77-LH-28-1 rescued the associative long- term potentiation impairment in the Dlg2+/- rats. Conclusions: Despite increasing synaptic NMDA receptor currents, the combined impact of reduced DLG2 impairs synaptic integration in dendrites resulting in disrupted associative synaptic plasticity. This biological phenotype can be reversed by compound classes used clinically such as muscarinic M1 receptor agonists and is therefore a potential target for therapeutic intervention.

Dendritic Integration Dysfunction in Neurodevelopmental Disorders

Neurodevelopmental disorders (NDDs) that affect cognition, social interaction, and learning, including autism spectrum disorder (ASD) and intellectual disability (ID), have a strong genetic component. Our current understanding of risk genes highlights two main groups of dysfunction: those in genes that act as chromatin modifiers and those in genes that encode for proteins localized at or near synapses. Understanding how dysfunction in these genes contributes to phenotypes observed in ASD and ID remains a major question in neuroscience. In this review, we highlight emerging evidence suggesting that dysfunction in dendrites – regions of neurons that receive synaptic input – may be key to understanding features of neuronal processing affected in these disorders. Dendritic integration plays a fundamental role in sensory processing, cognition, and conscious perception, processes hypothesized to be impaired in NDDs. Many high-confidence ASD genes function within dendrites where they control synaptic integration and dendritic excitability. Further, increasing evidence demonstrates that several ASD/ID genes, including chromatin modifiers and transcription factors, regulate the expression or scaffolding of dendritic ion channels, receptors, and synaptic proteins. Therefore, we discuss how dysfunction of subsets of NDD-associated genes in dendrites leads to defects in dendritic integration and excitability and may be one core phenotype in ASD and ID.

A conversion-type electrochemical artificial synapse for plasticity modulation and dendritic application

A conversion-type electrochemical artificial synapse exhibits potential applications for memory enhancement and dendritic integration; ultra-high sensitivity (3 mV) and extremely low-power consumption (32 fW) could be achieved.