Mild Traumatic Brain Injury Reduces Spine Density of Projection Neurons in the Medial Prefrontal Cortex and Impairs Extinction of Contextual Fear Memory

Abstract

Epidemiology studies have found that a comorbidity exists between traumatic brain injury (TBI) and stress-related disorders. However, the anatomical and cellular bases for this association is poorly understood. An inability to extinguish the memory of a traumatic event lies at the core of many stress-related disorders. Experimental studies have shown that the medial pre-frontal cortex (mPFC), especially the infralimbic (IL) cortex, is required for extinction and for storing the memory of extinction. The output from the central nucleus of amygdala projects to the lateral hypothalamus, paraventricular nucleus, and central gray to regulate heart rate, stress hormone release, and freezing behavior, respectively. Projection neurons of the IL (layers II/III pyramidal neurons) are thought to stimulate GABAergic neurons in the amygdala, which, in turn, inhibit central amygdala output and reduce fear expression. Thus, loss and/or altered morphology of projection neurons of IL as a result of a mild TBI (mTBI) can compromise their ability to effectively inhibit the central amygdala, allowing the original fear memory to drive behavior. Using lateral mild fluid percussion injury (mFPI) in rats, we found that mFPI did not reduce neuronal numbers in the IL, but caused a significant reduction in overall dendritic spine density of both basal and apical dendrites on layer II/III pyramidal neurons. Spine numbers on layer V/VI pyramidal neurons were not significantly changed as a result of mFPI. The reduction in spine density on layer II/III pyramidal neurons we observed may diminish the efficacy of these neurons to inhibit the output of the central amygdala, thereby reducing the ability of the IL to suppress fear responses after extinction training. Consistent with this, mFPI rats display enhanced freezing behavior during and after extinction training as compared to sham-operated controls, although the ability to form contextual fear memories was not impaired. These results may have implications in stress-related disorders associated with mTBI.

Screening for Traumatic Brain Injury in Prostituted Women

“…In a study of veterans with deployment-related TBI, 58% of the posttraumatic headaches were migraines (Otis et al, 2012). It is thought that the neural pathways for TBI, PTSD, and pain overlap considerably (Otis et al, 2012;Zhao et al, 2017). Pain may intensify PTSD by triggering traumatic memories (Otis et al, 2012).…”

“…Verfaellie et al (2012) suggest that the disruptions of memory, executive function, and verbal information processing that can be consequences of TBI may contribute to the development of PTSD. Animal research is beginning to elucidate the anatomic and cellular basis of this association (Zhao et al, 2017). Together, these considerations suggest that in addition to the inherent difficulties in distinguishing symptoms of TBI from symptoms of depression or PTSD in general populations, differential diagnosis may be particularly difficult with women who sustain TBI in prostitution because these women are likely to be at elevated risk for depression and PTSD relative to other people who sustain TBI.…”

Experimental Traumatic Brain Injury Induces Chronic Glutamatergic Dysfunction in Amygdala Circuitry Known to Regulate Anxiety-Like Behavior

“…Previously, we reported increased neuropathology in the somatosensory cortex and thalamus following dTBI, which could also alter sensory input into the BLA (Lisembee and Lifshitz, 2008;Thomas et al, 2018). Recent publications have also indicated subacute metabolic, and chronic metabolic and structural changes mapped directly to the CeA, and impairments in extinction of contextual fear differences at a chronic time point after experimental TBI (Zhao et al, 2018;Jaiswal et al, 2019;Kulkarni et al, 2019). In accordance with the data in this manuscript, these reports specifically identify the CeA as a vulnerable anatomic locus for future investigations, where FDA approved drugs with affinities for identified targets can be evaluated for new indications on their influence on glutamate signaling in anxiety-like behavior.…”

Guanfacine’s mechanism of action in treating prefrontal cortical disorders: Successful translation across species

“…Studies in rats have shown that TBI to the posterior cortex increases PKA signaling in the PFC ( Kobori et al, 2015 ), as well as reducing PFC spine density and impairing working memory ( Zhao et al, 2018 ). Thus, guanfacine treatment may be helpful to normalize intracellular signaling and promote synaptic strength.…”