Authentic Biochemistry

Fear-conditioning  learning is a low-threshold  enduring psychiatric  process that prepares a defense against dangerous phenomena and reduces the need to iteratively  relearn the signal. It is a pattern recognition response that can be modulated by experience and the severity of the stress signal and it is  a response that deteriorates in the elderly and in certain neuropsycoses  and anxiety disorders throughout life. Fear conditioning must be fluid  to readjust according to reverse learning.

 Persistent fear and avoidance of the potential for fear-associated events are common presentations of social anxiety disorder (SAD) and avoidant behavior  maintains SAD, thus it prevents the reversal of fear in social situations. The best treatment outcomes are CBT including exposure therapy, which leads to  fear extinction. Pharmacotherapy including  antidepressants, benzodiazepines, beta-blockers, anticonvulsants, or neuroleptics, are commonly administered with low efficacy.

Neuropeptide Y (NPY), a 36-amino acid peptide, is the most abundant and widely distributed neuropeptide in the mammalian brain and it may be  involved in social behavior and the fear circuitry, including activities in the amygdala, hippocampus, septum, periaqueductal gray, locus coeruleus, cerebral cortex, basal ganglia, hypothalamus, and thalamus. NPY is also a feeding simulant,  regulator of  blood pressure, bioenergetics , neuroendocrine hormone responses, neuronal excitability, and neuroplasticity including epigenetic mechanisms. Not surprisingly,  exogenous NPY  causes a variety of behavioral effects when administered into the brain of rodents including  stimulation of  food intake when administered into the hypothalamic paraventricular nucleus, and it promotes social interaction when administered into the dorsolateral septum and basolateral amygdala and has anxiolytic and antidepressant-like effects when administered intracerebroventricularly (i.c.v.).NPY also affects different aspects of fear-related behaviors, as shown in fear conditioning studies in rodents.

Next time we will link Acid Sphingomyelinase to NPY and the anxiety disorders of the elderly..

Int J Mol Sci. 2020 Nov; 21(21): 8220.

Homeostatic  chronic  low stress results in low to moderate levels of CRF in the LC in association with  enhanced Extra-Dimensional Shifting and optimal executive decision making. However, acute or chronic severe stress is linked to  high levels of CRF in the LC and this may  contribute to a shift from optimal executive function necessary for goal-directed behavior toward an iterative decision response. 

In healthy environments, this variable tonicity is a readout for adaptation  when goal-oriented behavior is relaxed so that the individual uses pro-forma decisions  even when novel environmental stimuli are encountered.

During aging these pathways lose flexibility due to a decrease in executive decision making linked to the senescence phenotype that may impair neural circuitry via inflammation, over or under activation and lack of control over  immune cell responses.

J Neurosci. 2008 Nov 5; 28(45): 11517–11525.

GeroScience. 2017 Feb; 39(1): 61–72.

Neuroscience. 2017 Mar 14; 345: 12–26.

Adaptation to stress-such as the fear response obtains dopaminergic input to striatum and prefrontal cortex and  is thought to signal unexpected events and facilitate a shift in attention to promote new learning within the contralateral primary somatosensory cortex (SI) which has been associated with the agentic categories of both the quality and quantity of thought event ontology. This process works in conjunction with  the bilateral secondary somatosensory cortex (SII) process  involved in executive  decision making. Where stimulated, the primary sensory motor-neuronal process  is integrated with novel extra-dimensional learning .

Recall that this fear stress response can lose functional valency upon immune-regulating, senescent secretory phenotypes.  

In the aging brain, where CRF axon terminals are widely distributed, (including within catecholamine and serotonin  nuclei) there are widespread cortical projections into the medial prefrontal cortex; linking  executive functional responses to adverse stimuli.

Dr. Daniel J. Guerra

Authentic Biochemistry

Published 20 Jan 2021

Refs

Neuroimage. 2008 May 1;40(4):1765-71.

Biol Psychiatry. 2009 Sep 15; 66(6): 586–593.

The anti-inflammatory IL-10 pathway in the CNS can lead to Glioblastoma which is a disease presented 3-4 fold higher in people ≥65 years old, and with a mortality rate for the same age group some 7 fold higher. Activation of the IL-10 Receptor bound ligand induces the JAK1 signal transducer and activator of transcription 3 (STAT3) pathway in APCs. This results in the subsequent translocation of STAT3 homodimers into the nucleus. This STAT3 homodimer binds to STAT-binding elements which promotes the expression of the suppressor of cytokine signaling 3 (SOCS-3) and IL-1 receptor antagonist (IL-1RN).  IL-10 reduces the production of pro-inflammatory cytokines (IL-1β, IL-6, tumor necrosis factor alpha) and diminished expression of both major histocompatibility complex II.

The anti-inflammatory  MiDAS phenotype can also induce heart failure in the aging population.

References:

Front Pharmacol. 2019; 10: 200

Aging Cell. 2018 Oct;17(5)

Int Heart J. 2018 Jul 31;59(4):837-844

Front. Immunol., 19 March 2018

Neuro Oncol . 2020 Mar 5;22(3):333-344

Non-uniform ageing is a major associative risk factor for cancer and degenerative diseases and mitochondrial dysfunction is linked to cellular senescence in association with cell cycle arrest, telomerase decline and nucleic acid/lipid/protein oxidation. Indeed, mitochondrial dysfunction comprises a distinct type of cellular senescence; mitochondrial SIRT3 or SIRT5, can induce Mitochondrial Dysfunction Associated-Senescence (MiDAS)

Senescence is a chronological and pathophysiological sequenced event response that restricts mitotic division and thus aberrant proliferation of damaged, infected and/or tumor inducing cells. Because these cells are senescent and exhibit low anabolic currency to present self-produced antigen epitopes as displayed by HLA, they are not targeted by immune responses but rather, may become secretory and induce inflammation by instantiating the Senescence Associated Secretory Phenotype-SASP. Senescence presents with metabolic reprogramming, epigenetic chromatin remodeling, and the secretion of growth factors, signaling molecules, proinflammatory cytokines and chemokines, extra-cellular matrix metallo proteases, nucleotides, exosomes and ionic bursts collectively referred to as SASP.

Both SASP and MiDAS can occur in the CNS during human aging thus generating a remarkably complex-contrarion dual pathophysiological phenotype leading to neurodegeneration or more rarely, certain forms of brain cancer.

Authentic Biochemistry Podcast is produced by Daniel J. Guerra, PhD.  Today's Date: 16 January 2021

Refs.

Trends in Biochemical Sciences Volume 41 Issue 3 Pages 207-209 (March 2016)

Cell Metabolism Volume 23, Issue 2, 9 February 2016, Pages 303-314

Front. Immunol., 19 March 2018

LC axonal projections to the mPFC modulate a diversity of cognitive processes, including working memory, sustained attention, and flexible attention and under moderate rates of LC activity and NE release, high-affinity postsvnaptic α2 adrenergic receptors in the PFC are preferentially engaged and promote working memory However, with elevated LC firing and activation of lower affinity α1 adrenergic receptors, working memory is impaired while agentic  focused attention becomes prominent so it seems that LC projections to the PFC modulate different cognitive processes in a context-sensitive manner.

his latter mechanism could correlate with the experienced rapid response such as in “fight or flee” decision making upon immediate threatening danger. The sensation perception recognition and response behaviour all works sequentially from these neuronal loci post encounter to the stimulus and as such fit well into Kantian epistemology which obtains that the individual is presented with a particular stimulus-sense data or “intuition” that is processed by the faculty of the understanding as a perception of danger in association with a concept-abstracted from previous experience. This representation is then acted upon and the neural network-already poised to respond sequentially follows suit and ultimately directs the motor cortex to act.

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•Intensive and chronic or excessive stress diminishes intellectual performance and general cognition: this is a form of negative reinforcement and can be related to learning disability and anxiety about future events. Indeed, •Individual responses and the magnitude of stressor as well as its association with self identity and goals will influence endurance, resilience, and self-empowerment vs. dissatisfaction and defeat.

•Stresses  first become recognized in the developing fetus since the fetal brain attains awareness during the first trimester and maternal stress is well established as an epigenetic mechanism involved in fetal neural development and  stress is lifelong , contributing to  one’s character and ability to overcome fear and anxiety.

•Stress response is an element of the hypothalamic-pituitary-adrenocortical (HPA) axis where  Corticotropin-releasing factor (CRF) serves as a gate keeper for fear conditioning playing dual roles as hormone and as neuromodulator.

•CRH exerts multiple effects on the adult brain, often spatiotemporal, as shown by secretion site-specific responses in that CRH after binding to its GPCR's: CRHR1 and CRHR2 which subsequently regulates the formation of neuronal dendrites; neurite elongation, synaptogenesis, and circuit integration of adult-born neurons thus organizing and modifying  excitatory transmission in a neuronal type-specific manner

Transl Psychiatry. 2019; 9: 272.

Cell Reports Oct 2019, 29, 932–945

1. Corticotropin releasing factor (CRF) or hormone (CRH) is one of several neurohormones synthesized by specific hypothalamic nuclei in the brain and released into the portal system which bathes the anterior pituitary

2. CRF has marked CNS effects by acting at higher centers in the brain: cortical regions where there is a widespread distribution of CRF neurons.

3. Major role of CRF is to prepare the organism for an appropriate response to various stressors such as physical trauma, insults to the immune system and social interactions

4. It is the hyper- or hyposensitivity of the system that can lead to human pathologies such as anxiety, depression and feeding disorders

5. The hypothalamus induced combined pituitary hormone deficiency, which  is responsible for  systemic hypoplasia is the result of a neutral sphingomyelinase (SMPD3)deficiency

6. SMPD3  deficiency triggers acid sphingomyelinase (ASM) plus de novo CER synthesis and salvage CER production  from sphingosine with concomitant alterations in membrane PLC mediated DAG enrichment of VLCPUFA’s and their SFA counterparts thus diturbing  membrane raft-mediated signaling and cell death and an appropriate local  immune response thus disturbing glucocorticoid (and a host of other) HPA axis hormones.

Naïve T Cell metabolic regulationinvolves allosteric and kinetic mechanisms for maximum capacity to switch from glucose uptake to fatty acylCoA utilization for bioenergetic demand.

Multiple mechanisms of this coordinated regulation involve the fatty acyl CoA concentration modulation by fine tuning cyctosolic fatty acid synthesis from glucose or lactate or amino acids vs. mitochondrial  beta oxidation to drive the ATP concentration to levels necessary to prepare for cell proliferation and evenbtually cytokine synthesis and secretion.

Published 06 January 2021.

Dr Daniel J. Guerra,  Authentic Biochemistry .

There is a requirement of cholesterol  and ceramides for the maintenance of neuronal  and T cell porosome integrity, accompanying  an interaction of phosphatidic acid (PA) and polyphosphoinositide (PI) lipids with syntaxin-1A where these lipids are necessary for neurotransmitter or cytokine secretion in association with calcium channels  modulated by lipid domain formation upon sphingomelinase and fatty acyltransferase activities. 

Complex lipid  composition and three dimensional sequence topology  differs between the inner and outer leaflet of the bilayer at descrete lipid raft domains of the endomembraneous and plasmamembrane where these  macromolecular structures contribute to the polarity of transport, access, and differential signaling uniquely essential for cell communication in the CNS and immune synapse.

Published on 05 Jan 2021 Authentic Biochemistry Dr Daniel J. Guerra, Ph.D.

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