Cholinergic markers are altered in two different models of traumatic brain injury

Traumatic brain injury (TBI) is the leading cause of death and disability in childhood, adolescence and early adulthood and often results in cognitive impairments. There is evidence from behavioural animal experiments and patient studies that those cognitive deficits are related to functional alterations within the cholinergic system. The present study was performed to investigate cholinergic markers in two different animal models of TBI with emphasis on the time-course of posttraumatic events and critical brain regions. The identification of sensitive targets within the cholinergic system is a precondition for the development of radioligands for neuroimaging of TBI patients with Positron-Emission-Tomography (PET).

Male Sprague-Dawley rats were randomized into three groups (post-TBI survival time: 2 h, 24 h and 72 h), anaesthetized and subjected to sham injury (control, n = 8) or controlled cortical impact injury (CCI) (n = 8) with 2 mm depth of impact at a velocity of 4 m/sec.
Thirteen newborn piglets (post-TBI survival time: 6 h) underwent fluid percussion (FP) injury (n = 7) or sham operation (n = 6) with an impact pressure of 3.8 ± 0.3 atmospheres.
For both species, cryostat brain sections were cut (rat 12 µm, pig 20 µm) and density of nicotinic (nAChR; α7, α4*/α3*), muscarinic (mAChR; M1-M5) acetylcholine receptors and the vesicular acetylcholine transporter (vAChT) were assessed with in vitro autoradiography. Additionally, histochemical staining of the acetylcholinesterase (AChE) was performed.

A significant decline in the receptor density of the α4*/α3* nAChR up to -33% was found in injured rats within brain regions critical for cognitive processes (thalamus, basal forebrain). In contrast, the brains of injured piglets did not reveal significant changes in receptor density.
The α7 nAChR density was drastically reduced (up to -47%) in injured rats at all time points and in piglets. Rats showed early decline of receptor density in 14 of 15 investigated brain regions (including hippocampus, thalamus, basal forebrain and cortex), while in piglets impairment was found especially in the hippocampus.
The mAChR showed smaller (~-20%), time-dependent reductions in injured rats and in piglets. However, almost identical brain regions were affected as found for α4*/α3* nAChR.
Histochemical staining indicated region-dependent increases and decreases in AChE activity in rats after TBI (~+/-20%) in contrast to injured piglets where only increased AChE-activity (+20%) was found.

In conclusion, cholinergic markers are significantly altered after experimental TBI independently of species, age and model. Even though differences in methodology do not allow direct comparisons between both models, results indicate common mechanisms of cholinergic changes after TBI. Considering the role of cholinergic markers for cognition in the brain, it seems likely that these alterations contribute to attention and memory deficits. Identifying the underlying mechanisms, for instance with PET, could help to ameliorate deficits in TBI-patients.