Traumatic Brain Injury-Induced Sex-Dependent Changes in Late-Onset Sensory Hypersensitivity and Glutamate Neurotransmission

Abstract

Women approximate one-third of the annual 2.8 million people in the United States who sustain traumatic brain injury (TBI). Several clinical reports support or refute that menstrual cycle-dependent fluctuations in sex hormones are associated with severity of persisting post-TBI symptoms. Previously, we reported late-onset sensory hypersensitivity to whisker stimulation that corresponded with changes in glutamate neurotransmission at 1-month following diffuse TBI in male rats. Here, we incorporated intact age-matched naturally cycling females into the experimental design while monitoring daily estrous cycle. We hypothesized that sex would not influence late-onset sensory hypersensitivity and associated in vivo amperometric extracellular recordings of glutamate neurotransmission within the behaviorally relevant thalamocortical circuit. At 28 days following midline fluid percussion injury (FPI) or sham surgery, young adult Sprague-Dawley rats were tested for hypersensitivity to whisker stimulation using the whisker nuisance task (WNT). As predicted, both male and female rats showed significantly increased sensory hypersensitivity to whisker stimulation after FPI, with females having an overall decrease in whisker nuisance scores (sex effect), but no injury and sex interaction. In males, FPI increased potassium chloride (KCl)-evoked glutamate overflow in primary somatosensory barrel cortex (S1BF) and ventral posteromedial nucleus of the thalamus (VPM), while in females the FPI effect was discernible only within the VPM. Similar to our previous report, we found the glutamate clearance parameters were not influenced by FPI, while a sex-specific effect was evident with female rats showing a lower uptake rate constant both in S1BF and VPM and longer clearance time (in S1BF) in comparison to male rats. Fluctuations in estrous cycle were evident among brain-injured females with longer diestrus (low circulating hormone) phase of the cycle over 28 days post-TBI. Together, these findings add to growing evidence indicating both similarities and differences between sexes in a chronic response to TBI. A better understanding of the influence of gonadal hormones on behavior, Krishna et al. Sex Influences TBI-Induced Behavior and Neurotransmission neurotransmission, secondary injury and repair processes after TBI is needed both clinically and translationally, with potential impact on acute treatment, rehabilitation, and symptom management.

Somatosensory dysfunction in patients with posttraumatic headache: A systematic review

“…Moreover, mice reacted hypersensitive to known migraine triggers after TBI, even after recovering from tactile hypersensitivity (19). Male and female rodents did not differ in sensitivity, but different specific transmitter and hormonal cycle changes were reported in females (20). Mild TBI led to a loss of diffuse noxious inhibitory control responses at an early time point after a TBI (21).…”

“…Again, in one study (9) this was only present in tension-type-like headaches. 19 Increased HPT and PPT (only in elderly) Not performed Reduced WPT Naugle et al, 2020 20 No uniformly change over all time points Reduced CPM effect Carey et al, 2019 21 Reduced PPT Reduced CPM effect Defrin et al, 2015 22 Increased HPT Reduced CPM effect Reduced PPT Defrin et al, 2010 23 Increased HPT Not performed Increased CPT Reduced PPT CPM: conditioned pain modulation, CPT: Cold pain threshold, HPT: Heat pain threshold, PPT: Pressure pain threshold, QST: Quantitative sensory testing, PTH: Posttraumatic headache, WPT: Warmth perception threshold. In contrast, pressure hypoalgesia was found in the elderly subjects in one study (26).…”

Spatial Distribution of Neuropathology and Neuroinflammation Elucidate the Biomechanics of Fluid Percussion Injury

“…With regard to the S1BF and ventral lateral thalamus, whisker hypersensitivity and somatosensory dysfunction have been reported. [30][31][32][33][34][35][36]67,[127][128][129] Cognitive performance involving short, long, and working memory, using multiple established mazes, is also impaired after FPI. 11,33,[37][38][39][40][41][42][43][44][45][46][47] These cognitive impairments may involve CA3 processing to perform object pattern completion, cue retrieval in fear conditioning, episodic memory, and spatial memory.…”

Sex-Dependent Pathology in the HPA Axis at a Sub-acute Period After Experimental Traumatic Brain Injury

“…Estrogen can indirectly affect astrocytes to contribute to neuroprotection by enhancing glutamine synthetase that can support glutamate neurotransmission (125). Furthermore, both estrogen and progesterone mediate anti-inflammatory, anti-oxidant, growth factor expression, and glutamate clearance properties that can be neuroprotective in astrocytes and may be linked to lower levels of GFAP staining intensity in sham and injured females compared to males (118,127).…”