Neurobiological consequences of acute footshock stress: effects on tyrosine hydroxylase phosphorylation and activation in the rat brain and adrenal medulla

Abstract

Stress activates selected neuronal systems in the brain and this leads to activation of a range of effector systems. Our aim was to investigate some of the relationships between these systems under basal conditions and over a 40-min period in response to footshock stress. Specifically, we investigated catecholaminergic neurons in the locus coeruleus (LC), ventral tegmental area and medial prefrontal cortex (mPFC) in the brain, by measuring tyrosine hydroxylase (TH) protein, TH phosphorylation and TH activation. We also measured the effector responses by measuring plasma adrenocorticotrophic hormone, corticosterone, glucose and body temperature as well as activation of adrenal medulla protein kinases, TH protein, TH phosphorylation and TH activation. The LC, ventral tegmental area and adrenal medulla all had higher basal levels of Ser19 phosphorylation and lower basal levels of Ser31 phosphorylation than the mPFC, presumably because of their cell body versus nerve terminal location, while the adrenal medulla had the highest basal levels of Ser40 phosphorylation. Ser31 phosphorylation was increased in the LC at 20 and 40 min and in the mPFC at 40 min; TH activity was increased at 40 min in both tissues. There were significant increases in body temperature between 10 and 40 min, as well as increases in plasma adrenocorticotropic hormone at 20 min and corticosterone and glucose at 20 and 40 min. The adrenal medulla extracellular signal-regulated kinase 2 was increased between 10 and 40 min and Ser31 phosphorylation was increased at 20 min and 40 min. Protein kinase A and Ser40 phosphorylation were increased only at 40 min. TH activity was increased between 20 and 40 min. TH protein and Ser19 phosphorylation levels were not altered in any of the brain regions or adrenal medulla over the first 40 min. These findings indicate that acute footshock stress leads to activation of TH in the LC, pre-synaptic terminals in the mPFC and adrenal medullary chromaffin cells, as well as changes in activity of the hypothalamic-pituitary-adrenal axis.

Neurotransmitter Systems in a Mild Blast Traumatic Brain Injury Model: Catecholamines and Serotonin

“…There are several reports on elevation of both TH and TPH2 following exposure to various other types of stressors. [80][81][82][83][84] Supporting our observations, Tümer and colleagues 85 also have reported significant increases in TH protein levels in the adrenal medulla (20%) and an even higher increase in nucleus tractus solitarii of the brain stem (49%), and showed that this increase is associated with elevated plasma norepinephrine levels (23%) 6 h post-exposure to blast. The authors have linked this upregulation of the sympathetic system to elevated oxidative stress in the hypothalamus.…”

Hypothalamic CNTF volume transmission shapes cortical noradrenergic excitability upon acute stress

“…Here, we find that recombinant CNTF induces significant Ser 31 phosphorylation of TH, along with prototypic Erk1 phosphorylation (Haycock et al , 1992) in cranial pons explants containing the LC (45 and 58% increase in the phosphorylated forms of TH and Erk, respectively, *P  <   0.05; Fig 3D–D2; Appendix Fig S2B). When applying subcutaneous formalin stress, Ser 31 phosphorylation of TH was transient (~twofold at 20 min, P  <   0.05) and eluded its Ser 40 residue, which seems unrelated to augmenting NE synthesis upon pain‐induced stress (Ong et al , 2014; Appendix Fig S2C and C1). To substantiate that ventricular ependyma is the source of CNTF to induce TH activity in LC, we performed site‐directed Cntf silencing through icv siRNA infusion (Fig 3E).…”

Getting to Compliance in Forced Exercise in Rodents: A Critical Standard to Evaluate Exercise Impact in Aging-related Disorders and Disease

“…Moreover, achieving 100% compliance in this regimen does not require the employment of electric footshock. Indeed, elimination of electric footshock is imperative in order to interpret the impact of exercise on behavioral measures that depend upon catecholamines, especially dopamine, given the long-known impact of stressors like footshook upon catecholamine biosynthesis 17–18 .…”

“…This is a critical point for consideration, particularly for those investigators involved in behavioral studies that are influenced by dopamine- or norepinephrine-signaling. Electrical footshock is a physiological stressor, and its impact on both neurotransmitter systems is well-documented, with increased activation of tyrosine hydroxylase 17–18 . Thus, increased biosynthesis of either neurotransmitter could confound the interpretation of any exercise effect, making the investigator liable for interpreting whether any observed change in behavior after exercise is strictly due to the exercise regimen or the footshock stress.…”