Deficits in Discrimination after Experimental Frontal Brain Injury Are Mediated by Motivation and Can Be Improved by Nicotinamide Administration

Abstract

One of the largest challenges in experimental neurotrauma work is the development of models relevant to the human condition. This includes both creating similar pathophysiology as well as the generation of relevant behavioral deficits. Recent studies have shown that there is a large potential for the use of discrimination tasks in rats to detect injury-induced deficits. The literature on discrimination and TBI is still limited, however. The current study investigated motivational and motor factors that could potentially contribute to deficits in discrimination. In addition, the efficacy of a neuroprotective agent, nicotinamide, was assessed. Rats were trained on a discrimination task and motivation task, given a bilateral frontal controlled cortical impact TBI (+3.0 AP, 0.0 ML from bregma), and then reassessed. They were also assessed on motor ability and Morris water maze (MWM) performance. Experiment 1 showed that TBI resulted in large deficits in discrimination and motivation. No deficits were observed on gross motor measures; however, the vehicle group showed impairments in fine motor control. Both injured groups were impaired on the reference memory MWM, but only nicotinamide-treated rats were impaired on the working memory MWM. Nicotinamide administration improved performance on discrimination and motivation measures. Experiment 2 evaluated retraining on the discrimination task and suggested that motivation may be a large factor underlying discrimination deficits. Retrained rats improved considerably on the discrimination task. The tasks evaluated in this study demonstrate robust deficits and may improve the detection of pharmaceutical effects by being very sensitive to pervasive cognitive deficits that occur after frontal TBI.

Combination therapies for neurobehavioral and cognitive recovery after experimental traumatic brain injury: Is more better?

“…Nicotinamide (NAM), the amide form of vitamin B 3 , increases the bioavailability of adenosine triphosphate in neurons and has been reported to benefit neurobehavioral, cognitive, and histological outcomes after TBI (Hoane et al, 2006, 2008; Vonder Haar et al, 2011, 2014). PROG has also been shown in numerous studies to confer significant benefits after experimental brain injury (Cutler et al, 2007; Cekic et al, 2009; Cekic and Stein, 2010; Stein and Cekic, 2011).…”

Vitamins and nutrients as primary treatments in experimental brain injury: Clinical implications for nutraceutical therapies

“…Specifically, NAM treatment has improved sensory, motor and cognitive function following frontal injury [66,74,198,200] and unilateral, sensorimotor cortex injury [52,75,77,144,148], with a time window of up to four hours [74,75]. Further, combination therapy with NAM and progesterone has shown additive effects, including reduced cell death, astrocyte activation, and substantially improved performance in multiple functional assessments [145].…”

“…Acutely (<7 days post injury), vitamin B 3 treatment reduced apoptosis, degenerating neurons, edema, and blood-brain barrier compromise, altered the number of activated astrocytes and decreased lesion size [70,73,80]. Chronically (> 20 days post injury), NAM treatment reduced lesion size and active astrocytes [52,66,74,75,77,144,198,200]. These neuroprotective effects of NAM are corroborated by brain injury studies specifically examining the downstream targets of NAM, namely the sirtuin receptor, supplementation of NAD + and inhibition of NAD phosphate oxidase, an enzyme involved in oxidative stress [7,46,207,229].…”

“…The reason is not immediately clear, but it is possible that these issues may be associated with actions at sirtuin receptors [154,222] or changes in free radical scavenging [113,222]. In addition to the challenge of aged populations, rodent models of TBI have shown that a 50 mg/kg dose was the minimum to show behavioral effects [74,75] and that to exhibit maximal recovery, a dose closer to 150–250 mg/kg per day may be necessary [144,145,198,200]. If this dose was translated directly to humans from the rodent model, it could possibly induce toxic reactions in humans, although doses as high as 80 mg/kg have been tolerated reasonably well [21,83].…”

Charting a course for erythropoietin in traumatic brain injury

“…These include targeting treatments with the mechanistic target of rapamycin (mTOR) [3,13], Wnt signaling pathways [24], nicotinamide [25–27], targets of oxidative stress [20,28], and sirtuins [29,30]. Yet, cytokines and growth factors offer interesting prospects for the treatment of TBI.…”