Early and Persistent Dendritic Hypertrophy in the Basolateral Amygdala following Experimental Diffuse Traumatic Brain Injury

Abstract

In the pathophysiology of traumatic brain injury (TBI), the amygdala remains understudied, despite involvement in processing emotional and stressful stimuli associated with anxiety disorders, such as post-traumatic stress disorder (PTSD). Because the basolateral amygdala (BLA) integrates inputs from sensory and other limbic structures coordinating emotional learning and memory, injury-induced changes in circuitry may contribute to psychiatric sequelae of TBI. This study quantified temporal changes in dendritic complexity of BLA neurons after experimental diffuse TBI, modeled by midline fluid percussion injury. At post-injury days (PIDs) 1, 7, and 28, brain tissue from sham and brain-injured adult, male rats was processed for Golgi, glial fibrillary acidic protein (GFAP), or silver stain and analyzed to quantify BLA dendritic branch intersections, activated astrocytes, and regional neuropathology, respectively. Compared to sham, braininjured rats at all PIDs showed enhanced dendritic branch intersections in both pyramidal and stellate BLA neuronal types, as evidenced by Sholl analysis. GFAP staining in the BLA was significantly increased at PID1 and 7 in comparison to sham. However, the BLA was relatively spared from neuropathology, demonstrated by an absence of argyrophilic accumulation over time, in contrast to other brain regions. These data suggest an early and persistent enhancement of dendritic complexity within the BLA after a single diffuse TBI. Increased dendritic complexity would alter information processing into and through the amygdala, contributing to emotional symptoms post-TBI, including PTSD.

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

“…However, in accordance with previous results published for the BLA 20 , silver staining did not reveal any evidence of overt neuropathology. Analysis of astrocytosis revealed that in contrast to our previous work in the BLA, astrocytes were not activated in the CeA following dTBI 20 . This indicates that CeA microglial activation is independent of the presence of pathology and may play an alternative role in the sequalae of events after TBI 69 .…”

“…No significant alterations were detected in the BLA in anesthetized rats in this study, although studies using focal TBI models indicate that BLA circuitry becomes weakened through altered neuronal excitability, changes in N-methyl-D-aspartate (NMDA) receptors, and changes to GABAergic production proteins (GAD-67), all of which may provide compensatory responses that primarily influence glutamate release in the CeA 20,64,65 . Previously, we reported increased neuropathology in the somatosensory cortex and thalamus following dTBI, which could also alter sensory input into the BLA 66,67 .…”

“…Robust astrocytosis in the BLA has been previously reported to be present at 7DPI and to resolve by 28DPI following experimental dTBI using mFPI 20 . Astrocytes may contribute to glutamate neurotransmission due to their role in clearance of glutamate from the extracellular space, and thus were analyzed using GFAP staining in the CeA.…”

Basolateral amygdala, nicotinic cholinergic receptors, and nicotine: Pharmacological effects and addiction in animal models and humans

“…Additionally, there is increased surface expression and function of α 7 nAChRs, expressed on somatodendritic regions of BLA glutamatergic neurons (Klein & Yakel, ). Another recent study found enhanced dendritic branch intersections in BLA pyramidal and stellate neurons, although BLA was relatively free of neuropathology compared to other brain regions (Hoffman et al., ). Enhanced dendritic complexity would affect the regulation of BLA neurocircuitry—probably disrupting the normal processing and perception of fear‐related stimuli.…”

Preclinical studies of stress, extinction, and prefrontal cortex: intriguing leads and pressing questions

“…Vyas and colleagues (Vyas et al 2004) demonstrated that the dendritic hypertrophy in basolateral amygdala resulting from chronic immobilization (2 h/day, 10 days) persists up to 21 days after the cessation of stress. Likewise, stellate and pyramidal neurons in the basolateral amygdala neurons undergo dendritic hypertrophy in as little as one day after traumatic brain injury (which may perhaps be considered a physiological stressor), which persists at least four weeks later, despite lack of neuronal loss in this structure (Hoffman et al 2017). Note, however, that the effect of stress on the basolateral amygdala may depend on intensity or modality of the stressor: others have found that daily restraint stress (6 h/day, 10 days) resulted in significant debranching and retraction of pyramidal neurons in basolateral amygdala (Grillo et al 2015), as did acute elevated platform stress (Maroun et al 2013).…”