The Anatomy of Memory and [potentially reversible] Erasure of Memory

is complex.

Learning and memory are two of the most magical capabilities of our mind.…………Thus, we are who we are in large part because of what we have learned and what we remember and forget. In this Review, we examine the molecular, cellular, and circuit mechanisms that underlie how memories are made, stored, retrieved, and lost.……………….Memory is the glue that holds our mental life together. Without its unifying power, both our conscious and unconscious life would be broken into as many fragments as there are seconds in the day. Our life would be empty and meaningless.Moreover, disturbances of memory can affect our cognitive capabilities and thus our quality of life at all stages of life. Early disorders of learning and memory hinder the development of children, the normal weakening of memory with time irritates and frustrates the aging, and the specter of Alzheimer disease haunts the elderly and their families. During the last four decades, neuroscience, the biological study of the brain, has succeeded in establishing a common conceptual framework that extends from cell and molecular biology, on the one hand, to brain system biology and psychology, on the other. Within this new, interdisciplinary structure, the scope of memory research ranges from genes to cognition, from molecules to mind.…………………………………. ……….…Unlike implicit memory, the conscious remembrance of things past requires a complex system involving the medial temporal lobe and the hippocampus. Cell 2014 Mar 27;157(1):163-86. doi: 10.1016/j.cell.2014.03.001. The molecular and systems biology of memory Eric R Kandel 1Yadin Dudai 2Mark R Mayford 3

Serotonin, neural markers, and memory

………”Notwithstanding neurotransmission systems are related to memory formation, amnesia and/or therapeutic targets for memory alterations, the role of transporters γ-aminobutyric acid (GABA, GAT1), glutamate (neuronal glutamate transporter excitatory amino acid carrier; EACC1), dopamine (DAT) and serotonin (SERT) is poorly understood.Serotonin, neural markers, and memory Alfredo Meneses* Front Pharmacol. 2015; 6: 143. Published online 2015 Jul 21. doi: 10.3389/fphar.2015.00143

The role of serotonin in memory: interactions with neurotransmitters and downstream signaling

Serotonin, or 5-hydroxytryptamine (5-HT), is found to be involved in many physiological or pathophysiological processes including cognitive function. Seven distinct receptors (5-HT1-7), each with several subpopulations, have been identified for serotonin, which are different in terms of localization and downstream signaling. Because of the development of selective agonists and antagonists for these receptors as well as transgenic animal models of cognitive disorders, our understanding of the role of serotonergic transmission in learning and memory has improved in recent years. A large body of evidence indicates the interplay between serotonergic transmission and other neurotransmitters including acetylcholine, dopamine, γ-aminobutyric acid (GABA) and glutamate, in the neurobiological control of learning and memory. In addition, there has been an alteration in the density of serotonergic receptors in aging and Alzheimer’s disease, and serotonin modulators are found to alter the process of amyloidogenesis and exert cognitive-enhancing properties. Here, we discuss the serotonin-induced modulation of various systems involved in mnesic function including cholinergic, dopaminergic, GABAergic, glutamatergic transmissions as well as amyloidogenesis and intracellular pathways. Mohammad Seyedabadi 1Gohar FakhfouriVahid RamezaniShahram Ejtemaei MehrReza Rahimian Review Exp Brain Res.  2014 Mar;232(3):723-38.  doi: 10.1007/s00221-013-3818-4. Epub 2014 Jan 16. The role of serotonin in memory: interactions with neurotransmitters and downstream signaling PMID: 24430027 DOI: 10.1007/s00221-013-3818-4

NB: This blogpost is a little messy because I am working through my main point by reading the following papers on [reversible] memory erasure, dentate granule cells, GABA inhibitory tone, and GABA effects on memory maintenance and respiratory depression and respiratory acidosis……..will need a little time…...will summarize these papers to make my point[s]. It is hard.

Rapid erasure of hippocampal memory following inhibition of dentate gyrus granule cells.

Abstract

The hippocampus is critical for the acquisition and retrieval of episodic and contextual memories. Lesions of the dentate gyrus, a principal input of the hippocampus, block memory acquisition, but it remains unclear whether this region also plays a role in memory retrieval. Here we combine cell-type specific neural inhibition with electrophysiological measurements of learning-associated plasticity in behaving mice to demonstrate that dentate gyrus granule cells are not required for memory retrieval, but instead have an unexpected role in memory maintenance. Furthermore, we demonstrate the translational potential of our findings by showing that pharmacological activation of an endogenous inhibitory receptor expressed selectively in dentate gyrus granule cells can induce a rapid loss of hippocampal memory. These findings open a new avenue for the targeted erasure of episodic and contextual memories. Nat Commun. 2016 Mar 18;7:10923. doi: 10.1038/ncomms10923. Rapid erasure of hippocampal memory following inhibition of dentate gyrus granule cells Noelia Madroñal 1 2José M Delgado-García 2Azahara Fernández-Guizán 2Jayanta Chatterjee 3Maja Köhn 3Camilla Mattucci 1Apar Jain 1Theodoros Tsetsenis 1Anna Illarionova 4Valery Grinevich 4Cornelius T Gross 1Agnès Gruart  PMID: 26988806 PMCID: PMC4802048 DOI: 10.1038/ncomms10923

Rapid erasure of episodic and contextual memory is what happened to Paula overnight, 20 or so years ago. Maintenance of long term personal memory was wiped out and eventually rescued intermittently within a year of taking an SSRI [Paxil] and rescued completely during a period of taking this SSRI for over ten years. Stopping the medication plunges Paula into amnesia and cognitive dulling all over again [within a few months] requiring the need to start the medication again in order to restore memory and cognition over the next couple of months. Paula has learnt the hard way that taking Paxil [30 mg] is necessary to maintain her normal memory and cognition.

Paxil works on many systems of the body, not just the brain. It is important to the metabolism of bone, muscle, and many parts of the skeletal motor/nerve system regulating the process of moving air in and out of healthy lungs. Paxil does not fix Paula’s broken ventilatory system [see past blog posts] but it seems to her that taking it every morning increases her *** endurance, which is important in her case because she exhaling actively and forcefully with her abdominal muscles with every breath, even at rest, especially at rest. No one really understands what Paxil does biochemically so we are left only with the personal observations of Paula in this case.

**** [Endurance refers to your body’s physical capability to sustain an exercise for an extended period. It’s made up of two components: cardiovascular endurance and muscular endurance.]

 The role of GABA-mediated inhibition is explained in the paper below;…………

Functional regulation of the dentate gyrus by GABA-mediated inhibition

Abstract

Dentate granule cells are characterized by their low levels of excitability, an important aspect of hippocampal function, which distinguishes them from other principal cells of the hippocampus. This low excitability derives in large part from the degree and nature of GABAergic inhibition evident in the dentate gyrus. Granule cells express a unique and complex assortment of GABA(A) receptor subunits, found in few areas of the brain. Associated with this receptor complexity, granule cells are endowed with both synaptic and extrasynaptic GABA(A) receptors with distinctive properties. In particular, extrasynaptic GABA(A) receptors in granule cells exhibit high affinity for GABA and do not desensitize. This results in activation of a tonic current by ambient levels of GABA present in the extracellular space. This tonic current contributes significantly to the circuit properties of the dentate gyrus. Both synaptic and extrasynaptic GABA(A) receptors exhibit profound dysregulation in animal models of temporal lobe epilepsy, which may contribute to the hippocampal hyperexcitability that defines this disorder. Prog Brain Res. Functional regulation of the dentate gyrus by GABA-mediated inhibition  2007;163:235-43. doi: 10.1016/S0079-6123(07)63014-3. Douglas A Coulter 1Gregory C Carlson PMID: 17765722 DOI: 10.1016/S0079-6123(07)63014-3

Decreased granule cell neurogenesis

Both epilepsy and depression show a disrupted production of adult-born hippocampal granule cells.[25] Epilepsy is associated with increased production – but aberrant integration – of new cells early in the disease and decreased production late in the disease. ……….…Unambiguous evidence of ongoing neurogenesis in mammals has revolutionized views of neuroplasticity in the adult brain. Neurogenesis is a natural feature of the mature brain, persisting into old age in both animals (Altman and Das, 1965Kaplan and Hinds, 1977van Praag et al., 2002) and humans (Eriksson et al., 1998). Ongoing production of hippocampal dentate granule cells has received much attention because of the role of the hippocampus in learning, memory and cognition (for review see Lisman, 1999Knierim et al., 2006Rolls and Kesner, 2006). Although it will take years of study to fully elucidate the purpose of these new cells, multiple lines of evidence indicate they are important for these key hippocampal functions (for review see Deng et al., 2010). In addition, emerging research implicates dysregulation of granule cell neurogenesis in several diseases, including depression and epilepsy. …………….Dentate granule cells are glutamatergic excitatory neurons that sit at the entrance to the hippocampus, acting as the intermediaries between entorhinal cortex and the hippocampal CA3 and CA1 pyramidal cells. The dentate, therefore, is ideally situated to act as a “gate”, limiting the amount excitatory input entering the hippocampus (Hsu et al., 2007). A key element of the dentate gate is evident from morphological studies by Acsády and colleagues (1998). Essentially, robust innervation of excitatory CA3 pyramidal cells by granule cells is offset by numerically superior innervation of GABAergic inhibitory interneurons by granule cells. The high ratio of inhibitory to excitatory contacts is unusual, being significantly greater than principal neurons in cortex (Acsády et al., 1998). The inhibitory neuron contacts of granule cells provide robust feedforward and feedback inhibition and serve as important structural components of the dentate gate (Lawrence and McBain, 2003). More direct evidence for the dentate gate has been provided by Ang and colleagues (2006), who were able to use voltage sensitive dyes to demonstrate invasion of neuronal activity into the dentate following activation of entorhinal afferents, and subsequent prevention of activity spread beyond the dentate. Finally, failure of this gating function is evident in several models of epilepsy (Heinemann et al., 1992Behr et al., 1998Gloveli et al., 1998Pathak et al., 2007Shao and Dudek, 2011). In part for this reason, a large body of literature in the epilepsy field has focused on the dentate (Dudek and Sutula, 2007). While there are many mechanisms in the brain for regulating the balance between excitation and inhibition, it appears that the ability of the dentate to control excitation is unusually pronounced and robust……………… Clearly, these ideas [about altered neurogenesis in both epilepsy and in depression] remain speculative, and even if altered neurogenesis does indeed contribute to the co-morbidity between depression and epilepsy, it is likely to be only one of many factors. Nonetheless, given the high incidence of depression in patients with epilepsy, and the neurogenic effects of all classes of antidepressant medications, it is important to understand the impact of these agents on the epileptic brain. Disruption of this gating function, therefore, may have disproportionate effects on the excitatory/inhibitory balance in the brain. Depression, stress, epilepsy and adult neurogenesis Steve C. Danzer Exp Neurol.  Exp Neurol. 2012 Jan; 233(1): 22–32. Published online 2011 Jun 12. doi: 10.1016/j.expneurol.2011.05.023

DISRUPTION OF TONIC INHIBITION of granular cells due to changes to GABA, may play a pivotal role in psychiatric disorders , such as anxiety and mood disorders.

Integration and regulation of glomerular inhibition in the cerebellar granular layer circuit

Inhibitory synapses can be organized in different ways and be regulated by a multitude of mechanisms. One of the best known examples is provided by the inhibitory synapses formed by Golgi cells onto granule cells in the cerebellar glomeruli. These synapses are GABAergic and inhibit granule cells through two main mechanisms, phasic and tonic. The former is based on vesicular neurotransmitter release, the latter on the establishment of tonic γ-aminobutyric acid (GABA) levels determined by spillover and regulation of GABA uptake. The mechanisms of post-synaptic integration have been clarified to a considerable extent and have been shown to differentially involve α1 and α6 subunit-containing GABA-A receptors. Here, after reviewing the basic mechanisms of GABAergic transmission in the cerebellar glomeruli, we examine how inhibition controls signal transfer at the mossy fiber-granule cell relay. First of all, we consider how vesicular release impacts on signal timing and how tonic GABA levels control neurotransmission gain. Then, we analyze the integration of these inhibitory mechanisms within the granular layer network. Interestingly, it turns out that glomerular inhibition is just one element in a large integrated signaling system controlled at various levels by metabotropic receptors. GABA-B receptor activation by ambient GABA regulates glutamate release from mossy fibers through a pre-synaptic cross-talk mechanisms, GABA release through pre-synaptic auto-receptors, and granule cell input resistance through post-synaptic receptor activation and inhibition of a K inward-rectifier current. Metabotropic glutamate receptors (mGluRs) control GABA release from Golgi cell terminals and Golgi cell input resistance and autorhythmic firing. This complex set of mechanisms implements both homeostatic and winner-take-all processes, providing the basis for fine-tuning inhibitory neurotransmission and for optimizing signal transfer through the cerebellar cortex.

Introduction

The fundamental anatomical and functional organization of the cerebellar cortex was defined since the ‘60s, thanks to improvements in anatomical and physiological techniques applied to the brain tissue (Eccles, 1967Palay and Chan-Palay, 1974). Golgi cells were shown to receive excitatory inputs from mossy fibers and parallel fibers and to inhibit granule cells. Granule cell excitation and inhibition were shown to occur inside the glomeruli, where each granule cell is contacted by mossy fiber terminals and in turn receives synapses from Golgi cells (Figure 1) (Hámori and Somogyi, 1983Jakab and Hámori, 1988). In 1964, Eccles, Llinas and Sasaki were the first to discover the GABAergic inhibitory nature of the Golgi cell-granule cell connection (Eccles et al., 1964), and the precise timing of excitation and inhibition in the circuit was reported (Eccles, 1967). REVIEW article Front. Cell. Neurosci., 25 February 2014 | https://doi.org/10.3389/fncel.2014.00055 Lisa Mapelli1,2Sergio Solinas1,2 and Egidio D’Angelo1,2

Abstract

GABAA receptors not only respond to the local release of GABA from presynaptic terminals, but can also mediate a persistent ‘tonic current’. This reflects the activation of high-affinity GABAAreceptors by ambient GABA concentrations. Tonic GABAA-receptor-mediated signalling occurs in different brain regions, shows cell-type-specific differences in magnitude and pharmacology, and changes during brain development. Some clues to the adaptive significance of this phenomenon are beginning to emerge: in cerebellar granule cells, it alters the gain of transmission of rate-coded sensory information; in the hippocampus, it acts in a cell-type-specific manner to regulate the excitability of the network. Because tonic conductances can be modulated by changes in GABA release and uptake, and by modulators of high-affinity GABAA receptors including neurosteroids, this phenomenon provides a potentially important new window onto neuronal information processing and pathological states such as epilepsy. Trends Neurosci. 2004 May;27(5):262-9. doi: 10.1016/j.tins.2004.03.005. Tonically active GABA A receptors: modulating gain and maintaining the tone Alexey Semyanov 1Matthew C WalkerDimitri M KullmannR Angus Silver PMID: 15111008 DOI: 10.1016/j.tins.2004.03.005

Granule cell [neurons]

The name granule cell has been used for a number of different types of neuron whose only common feature is that they all have very small cell bodies. Granule cells are found within the granular layer of the cerebellum, the dentate gyrus of the hippocampus, the superficial layer of the dorsal cochlear nucleus, the olfactory bulb, and the cerebral cortex. From Wikipedia, the free encyclopedia

GABA , wide-ranging effects on Memory Maintenance, control of breathing, and aging [development stages from cradle to grave].

Pathophysiological power of improper tonic GABAA conductances in mature and immature models

Regulation of Tonic Inhibition

After the finding of tonic inhibition in the mature brain (Kaneda et al., 1995), its functional significance for regulating network excitability was subsequently revealed. In CGCs, blocking tonic inhibition decreases membrane shunting (Brickley et al., 1996) and increases information flow from granule cells to Purkinje cells (Hamann et al., 2002). In thalamic relay neurons or hippocampal interneurons, baseline membrane potentials and network oscillation are modulated (Cope et al., 2005Song et al., 2011). Deregulation of tonic inhibition caused by a lack of synaptic plasticity-associated proteins has been shown in several mice models of neurological disorders (Curia et al., 2009Olmos-Serrano et al., 2010Egawa et al., 2012). However, the pathophysiological significance of long-term modification of extrasynaptic GABAA receptor activation can be masked by compensatory mechanisms (Brickley et al., 2001Wisden et al., 2002). Some adaptive regulation responses could be attributed to the modification of GABAA receptor trafficking and/or clustering on the membrane surface (Saliba et al., 2012; see review Hines et al., 2012). …….Regardless of the source of ambient GABA, GABA transporters play a pivotal role in regulating tonic inhibition. ………….Neurosteroids, metabolites of progesterone, other sex hormones, and several stress-induced steroids are potent modulators of GABAA receptors (Lambert et al., 2003). In particular, the extrasynaptic δ-GABAA receptor shows higher sensitivity for neurosteroids compared with synaptic GABAA receptors (Davies et al., 1997Stell et al., 2003; see review Brickley and Mody, 2012). ………Therefore, dysregulation of tonic inhibition may play a pivotal role in psychiatric disorders, such as anxiety and mood disorders, which are often associated with sex hormone alterations or stress. For example, expression of the δ subunit has been shown to decrease during pregnancy due to adaptive mechanisms against large elevation of progesterone metabolites (Maguire and Mody, 2008). The rapid decrease of neurosteroids after birth can thus induce the down-regulation of tonic inhibition, resulting in postpartum depression (Maguire and Mody, 2008). In a rat model of premenstrual dystrophic disorders, withdrawal of progesterone leads to anxiety and increased seizure susceptibility, associated with up-regulation of the α4 subunit (Smith et al., 1998). In contrast, increased levels of neurosteroids during physiological ovarian cycles leads to reduction of anxiety and seizure susceptibility caused by up-regulation of the δ subunit (Maguire et al., 2005). This difference may thus suggest that neurosteroids can alter the effects of tonic GABA conductance by dose and/or exposure time-dependent mechanisms, thereby regulating the expression of receptor subunits. In accordance with this speculation, evaluating anxiety at puberty revealed that neurosteroids negatively modulated tonic inhibition by decreasing outward currents, via α4δ-GABAA receptors (Shen et al., 2007). This regulation was shown to contribute to psychiatric disorders during puberty, such as mood swings, anxiety, and anorexia (Aoki et al., 2012).

Excessive stress leads to physiological and behavioral responses resulting in numerous psychiatric disorders. The hypothalamic-pituitary-adrenal (HPA) axis plays an important role for mediating physiological responses by promoting stress-induced steroid synthesis (see review Kudielka and Kirschbaum, 2005). A recent study has demonstrated that stress-derived neurosteroid acts on δ-GABAA receptors of corticotrophin releasing hormone (CRH) neurons, biphasically modulating their excitability depending on the presence or absence of stress (Hewitt et al., 2009). The study showed that stress decreased the activity of the outward-directed K+, Cl co-transporter, potassium-chloride transporter 2 (KCC2), in CRH neurons, switching tonic GABA conductance from inhibitory to excitatory and resulting in increased activity of the HPA axis and elevated levels of corticosterone (Hewitt et al., 2009). Because blockage of corticosterone synthesis prevents stress-induced anxiety, this positive feedback loop may be one of the mechanisms underlying stress-induced psychiatric disorders (Sarkar et al., 2011). Overall, emerging evidence has uncovered a bidirectional modification of tonic inhibition by neurosteroids, and thus may explain why increases in neurosteroids can lead to various types of psychiatric disorders, including depression and anxiety. Front. Neural Circuits, 24 October 2013 |  https://doi.org/10.3389/fncir.2013.00170 Kiyoshi Egawa1,2 and Atsuo Fukuda3* REVIEW article

The diversity of GABA receptors and the deregulation of GABA transporters disruption of tonic inhibition may explain changes to the electrical activity of neutrons and other cell types. This may explain the syndrome of remitting/relapsing syndrome of amnesia with psychomotor retardation [or with psychomotor excitement or mixed effects]. This may also explain adaptation and mechanical compensation of the skeletal pump system of ventilation in “control of breathing” issues due to permanent injury to the many parts of that system. It may explain how people like Paula are alive and often well despite their “broken breathing” with a baseline resting respiratory rate of 3 breaths per minute when healthy and active. Broken breathing of which they are unaware. Broken breathing which is not visible except by measuring respiratory rate. Measurements of respiratory rate will help to evaluate future risk of ventilatory failure [causing hypercapnic and dose related stages of potentially reversible brain failure during major respiratory challenges. Brain failure which will result in graded presentations of amnesia with cognitive dullness and psychomotor effects [same as locomotor subtypes of delirium-hypo, hyper and mixed activity subtypes].

More on GABA ………..

Abstract

GABAA receptors are ligand-gated chloride channels and ionotropic receptors of GABA, the main inhibitory neurotransmitter in vertebrates. In this review, we discuss the major and diverse roles GABAA receptors play in the regulation of neuronal communication and the functioning of the brain. GABAA receptors have complex electrophysiological properties that enable them to mediate different types of currents such as phasic and tonic inhibitory currents. Their activity is finely regulated by membrane voltage, phosphorylation and several ions. GABAA receptors are pentameric and are assembled from a diverse set of subunits. They are subdivided into numerous subtypes, which differ widely in expression patterns, distribution and electrical activity. Substantial variations in macroscopic neural behavior can emerge from minor differences in structure and molecular activity between subtypes. Therefore, the diversity of GABAA receptors widens the neuronal repertoire of responses to external signals and contributes to shaping the electrical activity of neurons and other cell types. Keywords: GABAA subtypes; Neuronal inhibition; Neurotransmitter; Phasic currents; Synaptic receptor; Tonic activity. Cell Mol Life Sci. Erwan Sallard 1 2Diane Letourneur 3 4Pascal Legendre . 2021 Jul;78(13):5341-5370. doi: 10.1007/s00018-021-03846-2.Epub 2021 Jun 1. PMID: 34061215 PMCID: PMC8257536 DOI: 10.1007/s00018-021-03846-2

,……The diversity of GABAA receptors widens the neuronal repertoire of responses to external signals and contributes to shaping the electrical activity of neurons and other cell types. ” Wow! That is truly fascinating. And may be the reason for the plasticity of the nervous system….

The diversity of GABA receptors and the deregulation of GABA transporters disruption of tonic inhibition may explain changes to the electrical activity of neutrons and other cell types. This may also explain adaptation and mechanical compensation of the skeletal pump system of ventilation in “control of breathing” issues due to permanent injury to the many parts of that system.

It may explain how people like Paula are alive and often well, despite their “broken breathing” with a baseline resting respiratory rate as low as 3 breaths per minute when healthy and active…. Broken breathing of which they are unaware….. Broken breathing which is not visible except by measuring respiratory rate. This may explain the syndrome of remitting/relapsing syndrome of amnesia with psychomotor retardation [or with psychomotor excitement or mixed effects] when this strong yet fragile system is overwhelmed by increased respiratory loads, especially under duress [infection and the ability to heal and recover from infection, for example].

Failure of physiological compensatory tactics most likely will result in development of metabolic disruption, maybe even hypercapnia, and and quiet delirium, which may look externally like major depression but involves unseen, unspoken amnesia and cognitive dullness in addition to psychomotor changes such as psychomotor retardation, psychomotor excitement and mixed signs and symptoms of different stages of ventilatory failure.

  • The paper below warrants a second look, since it is very important and describes Paula’s experience with her own sudden and “Rapid erasure of hippocampal memory” .

Rapid erasure of hippocampal memory following inhibition of dentate gyrus granule cells

Abstract

The hippocampus is critical for the acquisition and retrieval of episodic and contextual memories. Lesions of the dentate gyrus, a principal input of the hippocampus, block memory acquisition, but it remains unclear whether this region also plays a role in memory retrieval. Here we combine cell-type specific neural inhibition with electrophysiological measurements of learning-associated plasticity in behaving mice to demonstrate that dentate gyrus granule cells are not required for memory retrieval, but instead have an unexpected role in memory maintenance. Furthermore, we demonstrate the translational potential of our findings by showing that pharmacological activation of an endogenous inhibitory receptor expressed selectively in dentate gyrus granule cells can induce a rapid loss of hippocampal memory. …… Nat Commun. 2016 Mar 18;7:10923. doi: 10.1038/ncomms10923. Rapid erasure of hippocampal memory following inhibition of dentate gyrus granule cells Noelia Madroñal 1 2José M Delgado-García 2Azahara Fernández-Guizán 2Jayanta Chatterjee 3Maja Köhn 3Camilla Mattucci 1Apar Jain 1Theodoros Tsetsenis 1Anna Illarionova 4Valery Grinevich 4Cornelius T Gross 1Agnès Gruart  PMID: 26988806 PMCID: PMC4802048 DOI: 10.1038/ncomms10923

GABA seems key to a lot of body physiological systems……

GABA and Respiratory Depression

 “These results indicate that activation of GABA receptors causes respiratory depression . This suggests that GABA may be an important neurotransmitter in CNS neural pathways involved in regulating respiratory activity. J Appl Physiol Respir Environ Exerc Physiol 1981 Nov;51(5):1278-86.doi: 10.1152/jappl.1981.51.5.1278. Respiratory depression produced by activation of GABA receptors in hindbrain of cat K A YamadaP HamoshR A Gillis PMID: 6271715 DOI: 10.1152/jappl.1981.51.5.1278

Appl Physiol (1985)

Interdependence of neuromodulators in the control of breathing; Julius H. Comroe Distinguished Lecture:

Abstract

In vitro and in vivo anesthetized studies led to the conclusion that “deficiencies in one neuromodulator are immediately compensated by the action of other neuromodulators,” which suggests an interdependence among neuromodulators. This concept was the focus of the 2018 Julius H. Comroe Lecture to the American Physiological Society in which I summarized our published studies testing the hypothesis that if modulatory interdependence was robust, breathing would not decrease during dialysis of antagonists to G protein-coupled excitatory receptors or agonists to inhibitory receptors into the ventral respiratory column (VRC) or the hypoglossal motor nuclei (HMN). We found breathing was not decreased during unilateral VRC dialyses of antagonists to excitatory muscarinic, serotonergic, and neurokinin-1 receptors alone or in combinations nor was breathing decreased with unilateral VRC dialysis of a µ-opioid receptor agonist. Analyses of the effluent dialysate revealed locally increased serotonin (excitatory) during muscarinic receptor blockade and decreased γ-aminobutyric acid (inhibitory) during dialysis of opioid agonists, suggesting an interdependence of neuromodulators through release of compensatory neuromodulators. Bilateral dialysis of receptor antagonists or agonist in the VRC increased breathing, which does not support the concept that unchanged breathing with unilateral dialyses was due to contralateral compensation. In contrast, in the HMN neither unilateral nor bilateral dialysis of the excitatory receptor antagonists altered breathing, but unilateral dialysis of the opioid receptor agonist decreased breathing. We conclude: 1) there is site-dependent interdependence of neuromodulators during physiologic conditions, and 2) attributing physiologic effects to a specific receptor perturbation is complicated by local compensatory mechanisms. Keywords: breathing; compensation; neuromodulation.. 2018 Nov 1;125(5):1511-1525.doi: 10.1152/japplphysiol.00477.2018. Epub 2018 Aug 23. Interdependence of neuromodulators in the control of breathing; Julius H. Comroe Distinguished Lecture: Hubert V Forster 

  • Paula got her most serious attack of hidden amnesia and mental confusion with psychomotor retardation, 20+ years ago, during the time that she had to stop her progesterone birth control pills and during the start of the menopausal hormone changes. Maybe the article below explains why…..

The Aging GABAergic System and Its Nutritional Support

Abstract

Aging is associated with a decline in hormones and an associated decline in GABAergic function and calcium and ion current dysregulation. Neurosteroid hormones act as direct calcium channel blockers, or they can act indirectly on calcium channels through their interaction with GABA receptors. The calcium channel dysfunction associated with hormone loss further leads to an excitatory cell state, which can ultimately lead to cell death. The calcium theory of aging posits that cellular mechanisms, which maintain the homeostasis of cytosol Ca2+ concentration, play a key role in brain aging and that sustained changes in Ca2+ homeostasis provide the final common pathway for age-associated brain changes. There is a link between hormone loss and calcium dysregulation. Loss of calcium regulation associated with aging can lead to an excitatory cell state, primarily in the mitochondria and nerve cells, which can ultimately lead to cell death if not kept in check. A decline in GABAergic function can also be specifically tied to declines in progesterone, allopregnanolone, and DHEA levels associated with aging. This decline in GABAergic function associated with hormone loss ultimately affects GABAergic inhibition or excitement and calcium regulation throughout the body. In addition, declines in GABAergic function can also be tied to vitamin status and to toxic chemicals in the food supply. The decline in GABAergic function associated with aging has an effect on just about every body organ system. Nutritional support of the GABAergic system with supportive foods, vitamins, and GABA or similar GABA receptor ligands may address some of the GABAergic dysfunction associated with aging.

J Nutr Metab. . 2021 Apr 25;2021:6655064. doi: 10.1155/2021/6655064 .eCollection 2021. Demetra J Mills  PMID: 33986956 PMCID: PMC8093074 DOI: 10.1155/2021/6655064

Which brings us to our next blog post……

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