Biology subjects

Lifshitz, J.

Publications and source records attributed to Lifshitz, J..

5 recordsLinked to original sources

bioRxiv2026

Subacute and Chronic Cognitive and Cerebrovascular Functional Consequences of Mild Traumatic Brain Injury in Rats

Traumatic brain injury (TBI) is the main cause of death and disability in the United States in people younger than 35 years old and is a common cause of wartime injuries. Mild TBI (mTBI) is a predisposing factor for later development of dementia and cerebrovascular disease. Aerobic exercise was reported to improve cognitive function in chronic TBI through improved vascular function. The aims of the study are to characterize and correlate the subacute (10 weeks) and chronic (12 months) cognitive and cerebrovascular functional impairment following mTBI and evaluate the modulating effect of exercise early or late following mTBI on these changes. Sprague-Dawley rats received midline fluid percussion injury or sham procedure and followed for 10 weeks or 12 months with a subgroup of mTBI rats undergoing 5-week treadmill aerobic exercise 2 weeks (early) or 10 months (late) post-injury for 6 weeks. Cognitive function was assessed using novel object recognition (NOR) and novel object location (NOL) tests. Regional cerebral blood volume (CBV) and cerebrovascular reactivity following hypercapneic stimulation (CVR) using contrast magnetic resonance imaging (MRI) and ex vivo pial artery vasoreactivity to intraluminal pressure, angiotensin II and diethylenetriamine NONOate (DETA NONOate) were measured. There was no difference in NOR or NOL at 10 weeks between mTBI and sham. NOR, but not NOL, was reduced in mTBI rats at 12 months. CBV at 10 weeks was higher in the primary somatosensory trunk cortex (trunk) and dentate gyrus regions in mTBI, but not at 12 months. CVR was lower in the trunk region of mTBI rats at 12 months. Compared to sham response at 10 weeks, there was impaired arterial constriction response to 90 mm Hg intraluminal pressure in mTBI rats at 10 weeks and in sham and mTBI rats at 12 months, with no difference seen in response to angiotensin II or DETA-NONOate exposure. There was no correlation between cognitive and vascular outcomes at 10 weeks or 12 months. Early or late exercise did not affect 12-month cognitive or vascular function following mTBI. The study showed chronic impairment in short-term memory cognitive function, regional cerebrovascular reactivity and early onset of impaired cerebrovascular myogenic response in rats subjected to mTBI. The findings of persistent cognitive and cerebrovascular impairment in this animal model enhance our understanding of the long-term consequence of mTBI.

neuroscience↗

bioRxiv2022

Chronic Cognitive and Cerebrovascular Function Following Mild Traumatic Brain Injury in Rats

Severe traumatic brain injury results in cognitive dysfunction in part due to vascular perturbations. In contrast, the long-term vasculo-cognitive pathophysiology of mild TBI (mTBI) remains unknown. We evaluated mTBI effects on chronic cognitive and cerebrovascular function and assessed their interrelationships. Sprague-Dawley rats received midline fluid percussion injury (N=20) or sham (N=21). Cognitive function was assessed (3- and 6-month novel object recognition (NOR), novel object location (NOL) and temporal order object recognition (TOR)). 6-month cerebral blood flow (CBF) and blood volume (CBV) using contrast MRI and ex vivo pial artery endothelial and smooth muscle-dependent function were measured. mTBI rats showed impaired NOR, with similar (non-significant) trends in NOL/TOR. Regional CBF and CBV were similar in sham and mTBI. NOR correlated with CBF in lateral hippocampus, medial hippocampus and primary somatosensory barrel cortex while inversely correlating with arterial smooth muscle-dependent dilation. 6-month baseline endothelial and smooth muscle-dependent arterial function were similar among mTBI and sham, but post-angiotensin II stimulation, mTBI showed no change in smooth muscle-dependent dilation from baseline response, unlike the reduction in sham. mTBI led to chronic cognitive dysfunction and altered angiotensin II-stimulated smooth muscle-dependent vasoreactivity, a paradigm that could advance understanding of the long-term sequelae of human mild TBI.

neuroscience↗

bioRxiv2020

Spatial distribution of neuropathology and neuroinflammation elucidate the biomechanics of fluid percussion injury

Diffuse brain injury is better described as multi-focal, where pathology can be found adjacent to seemingly uninjured neural tissue. In experimental diffuse brain injury, pathology and pathophysiology have been reported far more lateral than predicted by the impact site. Finite element biomechanical models of diffuse brain injury predict regions of maximum stress and strain. However, the application of a skull with uniform thickness may mask the pathophysiology due to varying thickness of human and animal skulls. Force applied to the intact skull would diffuse the forces, whereas forces applied through an open skull are distributed along paths of least resistance within and then exiting the skull. We hypothesized that the local thickening of the rodent skull at the temporal ridges serves to focus the intracranial mechanical forces experienced during brain injury and generate predictable pathology in underlying cortical tissue. We demonstrated local thickening of the skull at the temporal ridges using contour analysis of coronal skull sections and oblique sectioning on MRI. After diffuse brain injury induced by midline fluid percussion injury (mFPI), pathological foci along the anterior-posterior length of cortex under the temporal ridges were evident acutely (1, 2, 7 days) and chronically (28 days) post-injury by deposition of argyophilic reaction product. Area CA3 of the hippocampus and lateral nuclei of the thalamus showed pathological change, suggesting that mechanical forces to or from the temporal ridges shear subcortical regions. A proposed model of mFPI biomechanics suggests that injury force vectors reflect off the skull base and radiate toward the temporal ridge due to the material properties of the skull based on thickness, thereby injuring ventral thalamus, dorsolateral hippocampus, and sensorimotor cortex. Surgically thinning the temporal ridge prior to injury reduced the injury-induced inflammation in sensorimotor cortex. These data build evidence for the temporal ridges of the rodent skull to contribute to the observed pathology, whether by focusing extracranial forces to enter the cranium or intracranial forces to escape the cranium. Pre-clinical investigations can take advantage of the predicted pathology to explore injury mechanisms and treatment efficacy. HighlightsO_LIThe temporal ridge is 75% thicker than the adjacent skull of the rodent C_LIO_LIExperimental diffuse TBI neuropathology occurs beneath the length of the temporal ridge C_LIO_LINeuropathology encompasses sensorimotor cortex, somatosensory thalamus, and dorsolateral hippocampus C_LIO_LIProposed mechanism of biomechanical injury forces include the temporal ridge C_LI

neuroscience↗

bioRxiv2019

Sex-dependent macromolecule and nanoparticle delivery in experimental brain injury

Development of effective therapeutics for brain disorders is challenging, in particular, the blood-brain barrier (BBB) severely limits access of the therapeutics into the brain parenchyma. Traumatic brain injury (TBI) may lead to transient BBB permeability that affords a unique opportunity for therapeutic delivery via intravenous administration ranging from macromolecules to nanoparticles (NP) for developing precision therapeutics. In this regard, we address critical gaps in understanding the range/size of therapeutics, delivery window(s), and moreover the potential impact of biological factors for optimal delivery parameters. Here we show, for the first time, to the best of our knowledge, that 24 h post-focal TBI female mice exhibit a heightened macromolecular tracer and NP accumulation compared to male mice, indicating sex-dependent differences in BBB permeability. Furthermore, we report for the first time the potential to deliver NP-based therapeutics within 3 d after focal injury in both female and male mice. The delineation of injury-induced BBB permeability with respect to sex and temporal profile is essential to more accurately tailor time-dependent precision and personalized nanotherapeutics.

bioengineering↗

bioRxiv2019

Diffuse TBI-induced expression of anxiety-like behavior coincides with altered glutamatergic function, TrkB protein levels and region-dependent pathophysiology in amygdala circuitry

Up to 50% of traumatic brain injury (TBI) survivors demonstrate persisting affective symptoms indicative of limbic system dysregulation, yet the pathophysiology underlying the symptoms is unclear. We hypothesize that TBI-induced pathophysiologic changes within distinct amygdala nuclei contribute to the expression of late-onset anxiety-like behavior. Adult, male Sprague-Dawley rats underwent midline fluid percussion injury or sham surgery. Anxiety-like behavior was assessed at 7 and 28 days post-injury (DPI) followed by assessment of real-time glutamate neurotransmission in the basolateral amygdala (BLA) and central nucleus of the amygdala (CeA) using glutamate-selective microelectrode arrays. In separate animal cohorts, the presence of neuropathology, astrocytosis, and microglial activation were assessed at 1, 7, and 28DPI. Protein levels of glutamatergic transporters (Glt-1, GLAST) and presynaptic modulators of glutamate release (mGluR2, TrkB, BDNF, and glucocorticoid receptors) were quantified using automated capillary western techniques at 28DPI. The expression of anxiety-like behavior at 28DPI coincided with decreased glutamate release and slower glutamate clearance in the CeA, not BLA. Changes in glutamate neurotransmission were independent of protein levels of glutamate transporters and mGluR2 receptors, neuropathology, and astrocytosis. At 1DPI, microglia in the CeA demonstrated a neuroinflammatory response. BDNF and TrkB were decreased at 28DPI in the amygdala. These data indicate that diffuse axonal injury instigates sequences of molecular, structural and functional changes in the amygdala that contribute to circuit dysregulation relevant to the expression of affective disorders. Translationally, diffuse axonal injury can influence severity and incidence of affective symptoms and should be addressed in the history of patients with affective disorders.

neuroscience↗