Developmental alcohol exposure causes a host of cognitive and neuroanatomical abnormalities, one of which is impaired executive functioning resulting from medial prefrontal cortex (mPFC) damage. This study determined whether third-trimester equivalent alcohol exposure reduced the number of mPFC GABAergic parvalbumin-positive (PV+) interneurons, hypothesized to play an important role in local inhibition of the mPFC. The impact on passive avoidance learning and the therapeutic role of aerobic exercise in adulthood was also explored. Male C57BL/6J mice received either saline or 5 g/kg ethanol (two doses, two hours apart) on PD5, 7, and 9. On PD35, animals received a running wheel or remained sedentary for 48 days before behavioral testing and perfusion on PD83. The number of PV+ interneurons was stereologically measured in three separate mPFC subregions: infralimbic, prelimbic and anterior cingulate cortices (ACC). Neonatal alcohol exposure decreased number of PV+ interneurons and volume of the ACC, but the other regions of the mPFC were spared. Alcohol impaired acquisition, but not retrieval of passive avoidance, and had no effect on motor performance on the rotarod. Exercise had no impact on PV+ cell number, mPFC volume, or acquisition of passive avoidance, but enhanced retrieval in both control and alcohol-exposed groups, and enhanced rotarod performance in the control mice. Results support the hypothesis that part of the behavioral deficits associated with developmental alcohol exposure are due to reduced PV+ interneurons in the ACC, but unfortunately exercise does not appear to be able to reverse any of these deficits.
Prenatal alcohol exposure can produce permanent alterations in brain structure and profound behavioral deficits. Mouse models can help discover mechanisms and identify potentially useful interventions. This study examined long-term influences of either a single or repeated alcohol exposure during the third-trimester equivalent on survival of new neurons in the hippocampus, behavioral performance on the Passive avoidance and Rotarod tasks, and the potential role of exercise as a therapeutic intervention. C57BL/6J male mice received either saline or 5 g/kg ethanol split into two s.c. injections, two hours apart, on postnatal day (PD)7 (Experiment 1) or on PD5, 7 and 9 (Experiment 2). All mice were weaned on PD21 and received either a running wheel or remained sedentary from PD35-PD80/81. From PD36-45, mice received i.p. injections of 50 mg/kg bromodeoxyuridine (BrdU) to label dividing cells. Behavioral testing occurred between PD72-79. Number of surviving BrdU+ cells and immature neurons (doublecortin; DCX+) were measured at PD80-81. Alcohol did not affect number of BrdU+ or DCX+ cells in either experiment. Running significantly increased number of BrdU+ and DCX+ cells in both treatment groups. Alcohol-induced deficits on Rotarod performance and acquisition of the Passive avoidance task (Day 1) were evident only in Experiment 2 and running rescued these deficits. These data suggest neonatal alcohol exposure does not result in long-term impairments in adult hippocampal neurogenesis in the mouse model. Three doses of ethanol were necessary to induce behavioral deficits. Finally, the mechanisms by which exercise ameliorated the neonatal alcohol induced behavioral deficits remain unknown.
In laboratory time-based prospective memory tasks, older adults typically perform worse than younger adults do. It has been suggested that less frequent clock checking due to problems with executive functions may be responsible. We aimed to investigate the role of clock checking in older adults’ time-based prospective memory and to clarify whether executive functions would be associated with clock checking and consequently, with time-based prospective memory. We included 62 healthy older adults (62-85 years of age) and applied tasks of time-based prospective memory as well as of executive functions (i.e., inhibition, fluency, and working memory). We used mediation analysis to test whether time-based prospective memory declined with advancing age due to less frequent clock checking. In addition, we tested whether there would be an association between executive functions and clock checking or time-based prospective memory. Time-based prospective memory declined with advancing age due to less frequent clock checking within 30s prior to intention completion. We only found a link between executive functions and clock checking (or time-based prospective memory) when not controlling for age. Our results support the importance of clock checking for time-based prospective memory and add to the current literature that older adults’ prospective memory declines because they are less able to adapt their clock checking. Yet, the reason why older adults are less able to adapt their clock checking still remains open. Our results do not indicate that executive function deficits play a central role.
Background Alzheimer’s disease (AD) is a major public health issue. Cognitive interventions such as computerized cognitive trainings (CCT) are effective in attenuating cognitive decline in AD. However, in those at risk of dementia related to AD, results are heterogeneous. Efficacy and feasibility of CCT needs to be explored in depth. Moreover, underlying mechanisms of CCT effects on the three cognitive domains typically affected by AD (episodic memory, semantic memory and spatial abilities) remain poorly understood. Methods In this bi-centric, randomized controlled trial (RCT) with parallel groups, participants (planned N = 162, aged 60–85 years) at risk for AD and with at least subjective cognitive decline will be randomized to one of three groups. We will compare serious game-based CCT against a passive wait list control condition and an active control condition (watching documentaries). Training will consist of daily at-home sessions for 10 weeks (50 sessions) and weekly on-site group meetings. Subsequently, the CCT group will continue at-home training for an additional twenty-weeks including monthly on-site booster sessions. Investigators conducting the cognitive assessments will be blinded. Group leaders will be aware of participants’ group allocations. Primarily, we will evaluate change using a compound value derived from the comprehensive cognitive assessment for each of three cognitive domains. Secondary, longitudinal functional and structural magnetic resonance imaging (MRI) and evaluation of blood-based biomarkers will serve to investigate neuronal underpinnings of expected training benefits. Discussion The present study will address several shortcomings of previous CCT studies. This entails a comparison of serious game-based CCT with both a passive and an active control condition while including social elements crucial for training success and adherence, the combination of at-home and on-site training, inclusion of booster sessions and assessment of physiological markers. Study outcomes will provide information on feasibility and efficacy of serious game-based CCT in older adults at risk for AD and will potentially generalize to treatment guidelines. Moreover, we set out to investigate physiological underpinnings of CCT induced neuronal changes to form the grounds for future individually tailored interventions and neuro-biologically informed trainings. Trial registration This RCT was registered 1st of July 2020 at clinicaltrials.gov (Identifier NCT04452864).
Background Recent studies suggest that computerized puzzle games are enjoyable, easy to play, and engage attentional, visuospatial, and executive functions. They may help mediate impairments seen in cognitive decline in addition to being an assessment tool. Eye tracking provides a quantitative and qualitative analysis of gaze, which is highly useful in understanding visual search behavior. Objective The goal of the research was to test the feasibility of eye tracking during a puzzle game and develop adjunct markers for cognitive performance using eye-tracking metrics. Methods A desktop version of the Match-3 puzzle game with 15 difficulty levels was developed using Unity 3D (Unity Technologies). The goal of the Match-3 puzzle was to find configurations (target patterns) that could be turned into a row of 3 identical game objects (tiles) by swapping 2 adjacent tiles. Difficulty levels were created by manipulating the puzzle board size (all combinations of width and height from 4 to 8) and the number of unique tiles on the puzzle board (from 4 to 8). Each level consisted of 4 boards (ie, target patterns to match) with one target pattern each. In this study, the desktop version was presented on a laptop computer setup with eye tracking. Healthy older subjects were recruited to play a full set of 15 puzzle levels. A paper-pencil–based assessment battery was administered prior to the Match-3 game. The gaze behavior of all participants was recorded during the game. Correlation analyses were performed on eye-tracking data correcting for age to examine if gaze behavior pertains to target patterns and distractor patterns and changes with puzzle board size (set size). Additionally, correlations between cognitive performance and eye movement metrics were calculated. Results A total of 13 healthy older subjects (mean age 70.67 [SD 4.75] years; range 63 to 80 years) participated in this study. In total, 3 training and 12 test levels were played by the participants. Eye tracking recorded 672 fixations in total, 525 fixations on distractor patterns and 99 fixations on target patterns. Significant correlations were found between executive functions (Trail Making Test B) and number of fixations on distractor patterns (P=.01) and average fixations (P=.005). Conclusions Overall, this study shows that eye tracking in puzzle games can act as a supplemental source of data for cognitive performance. The relationship between a paper-pencil test for executive functions and fixations confirms that both are related to the same cognitive processes. Therefore, eye movement metrics might be used as an adjunct marker for cognitive abilities like executive functions. However, further research is needed to evaluate the potential of the various eye movement metrics in combination with puzzle games as visual search and attentional marker.
New neurons are continuously generated in the adult hippocampus but their function remains a mystery. The nestin thymidine kinase (nestin-TK) transgenic method has been used for selective and conditional reduction of neurogenesis for the purpose of testing the functional significance of new neurons in learning, memory and motor performance. Here we explored the nestin-TK model on a hybrid genetic background (to increase heterozygosity, and “hybrid vigor”). Transgenic C57BL/6J (B6) were crossed with 129S1/SvImJ (129) producing hybrid offspring (F1) with the B6 half of the genome carrying a herpes simplex virus thymidine kinase (TK) transgene regulated by a modified nestin promoter. In the presence of exogenously administered valganciclovir, new neurons expressing TK undergo apoptosis. Female B6 nestin-TK mice (n = 80) were evaluated for neurogenesis reduction as a positive control. Male and female F1 nestin-TK mice (n = 223) were used to determine the impact of neurogenesis reduction on the Morris water maze (MWM) and rotarod. All mice received BrdU injections to label dividing cells and either valganciclovir or control chow, with or without a running wheel for 30 days. Both the F1 and B6 background displayed approximately 50% reduction in neurogenesis, a difference that did not impair learning and memory on the MWM or rotarod performance. Running enhanced neurogenesis and performance on the rotarod but not MWM suggesting the F1 background may not be suitable for studying pro-cognitive effects of exercise on MWM. Greater reduction of neurogenesis may be required to observe behavioral impacts. Alternatively, new neurons may not play a critical role in learning, or compensatory mechanisms in pre-existing neurons could have masked the deficits. Further work using these and other models for selectively reducing neurogenesis are needed to establish the functional significance of adult hippocampal neurogenesis in behavior.
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