Novel Social Stimulation Ameliorates Memory Deficit in Alzheimer's Disease Model through Activating α-Secretase.

As the most common form of dementia in the world, Alzheimer's disease (AD) is a progressive neurological disorder marked by cognitive and behavioral impairment. According to previous researches, abundant social connections shield against dementia. However, it is still unclear how exactly social interactions benefit cognitive abilities in people with AD and how this process is used to increase their general cognitive performance. In this study, we found that single novel social (SNS) stimulation promoted c-Fos expression and increased the protein levels of mature ADAM10/17 and sAPPα in the ventral hippocampus (vHPC) of wild-type (WT) mice, which are hippocampal dorsal CA2 (dCA2) neuron activity and vHPC NMDAR dependent. Additionally, we discovered that SNS caused similar changes in an AD model, FAD4T mice, and these alterations could be reversed by α-secretase inhibitor. Furthermore, we also found that multiple novel social (MNS) stimulation improved synaptic plasticity and memory impairments in both male and female FAD4T mice, accompanied by α-secretase activation and Aß reduction. These findings provide insight into the process underpinning how social interaction helps AD patients who are experiencing cognitive decline, and we also imply that novel social interaction and activation of the α-secretase may be preventative and therapeutic in the early stages of AD.

Deconstructing the function of maternal stimulation in offspring development: Insights from the artificial rearing model in rats.

This article is part of a Special Issue on "Parental Care". Maternal behavior has an important function in stimulating adequate growth and development of the young. Several approaches have been used in primates and rodents to deconstruct and examine the influence of specific components of maternal stimulation on offspring development. These approaches include observational studies of typical mother-infant interactions and studies of the effects of intermittent or complete deprivation of maternal contact. In this review, we focus on one unique approach using rats that enables the complete control of maternal variables by means of rearing rat pups artificially without contact with the mother or litter, while maintaining stable nutrition, temperature and exposure to stressful stimuli. This artificial rearing model permits the removal and controlled replacement of relevant maternal and litter stimuli and has contributed valuable insights regarding the influence of these stimuli on various developmental outcomes. It also enables the analysis of factors implicated in social isolation itself and their long-term influence. We provide an overview of the effects of artificial rearing on behavior, physiology, and neurobiology, including the influence of replacing maternal tactile stimulation and littermate contact on these outcomes. We then discuss the relevance of these effects in terms of the maternal role in regulating different aspects of offspring development and implications for human research. We emphasize that artificial rearing of rats does not lead to a global insult of nervous system development, making this paradigm useful in investigating specific developmental effects associated with maternal stimulation.

A Social Stimulation Paradigm to Ameliorate Memory Deficit in Alzheimer's Disease.

Alzheimer's disease (AD) poses a global health threat, progressively robbing patients of their memory and cognitive abilities. While it is recognized that meaningful social contact can alleviate the symptoms of dementia in AD patients, the precise mechanisms by which social stimulation mitigates AD symptoms remain poorly understood. We found that social interaction with novel mice, also known as novel social, simulated meaningful socializing. Therefore, we developed the multiple novel social (MNS) stimulation paradigm to train AD model mice and found that MNS effectively alleviated cognitive deficits in AD mice. This discovery not only opens up a new avenue for investigating the relationship between social stimulation and Alzheimer's disease but also lays the groundwork for delving into the underlying mechanisms, thereby providing crucial theoretical support for developing novel strategies to treat Alzheimer's disease. Key features • Designing a new social stimulation method to simulate meaningful social interactions in daily life. • The MNS stimulation protocol spans 14 days, with one novel mouse introduced to the subject mice each day. • The subjects were 2.5-month-old FAD4T mice, simulating patients with mild cognitive impairment (MCI). • Results of behavioral tests confirm the efficacy of MNS in reducing cognitive deficits in the AD model. This protocol is used in: J Neurosci (2024), DOI: 10.1523/JNEUROSCI.1689-23.2024.

Environmental enrichment accelerates the acquisition of schedule-induced drinking in rats.

Environmental enrichment (EE) provides an improvement in the housing conditions of experimental animals, such as laboratory rats, with greater physical and social stimulation through toys and company in the home cages. Its use is known to influence performance of experimental protocols, but these effects have not been well determined in the schedule-induced drinking (SID) procedure. The main goal of this study was to investigate the effects of EE on the acquisition of SID in 24 12-week-old male Wistar rats, divided into two groups, a group with EE housed with toys and companions, and a group without enrichment in individual housing conditions without toys (social isolation and no environmental enrichment, INEE). A total of 25 sessions, under a fixed time 30 s food reinforcement schedule and with access to water in the experimental chambers were carried out. Sessions lasted 30 min. The results showed that the EE group developed faster the excessive drinking pattern of SID, and drank to higher levels, than the INEE group. The greater development of SID in the EE group contradicts the view of schedule-induced behavior as linked to stress reduction and better suits with the conception of induction related to positive reinforcement.

Audience effects in a group-living bird: How contact call rate is affected by vegetation and group size and composition.

Contact calling is a ubiquitous behavior of group-living animals. Yet in birds, beyond a general connection with group cohesion, its precise function is not well-understood, nor is it clear what stimulates changes in contact call rate. In an aviary experiment, we asked whether Swinhoe's White-eyes, Zosterops simplex, would regulate their own production of contact calls to maintain a specific rate at the group level. Specifically, we hypothesized that the sudden cessation of the group-level call rate could indicate an immediate predation threat, and we predicted that birds in smaller groups would call more to maintain a high call rate. We also investigated the effects of environmental characteristics, such as vegetation density, and social stimuli, such as the presence of certain individuals, on the rate of three different contact call types. To calculate mean individual-level rates, we measured the group-level rate and divided it by the number of birds in the aviary. We found that the individual-level rate of the most common call types increased with a greater group size, the opposite pattern to what would be expected if birds were maintaining a specific group-level rate. Vegetation density did not affect any call rate. However, individual-level rates of all call types decreased when birds were in subgroups with individuals of differing dominance status, and the rate of some call types increased when birds were with affiliated individuals. Our results do not support the hypothesis that contact calls are related to habitat structure or immediate predation risk. Rather, they appear to have a social function, used for communication within or between groups depending on the call type. Increases in call rates could recruit affiliated individuals, whereas subordinates could withhold calls so that dominants are unable to locate them, leading to fluctuations in contact calling in different social contexts.

Effects of integrated psychosocial stimulation (PS) and Unconditional Cash Transfer (UCT) on Children's development in rural Bangladesh: A cluster randomized controlled trial.

BACKGROUND: There is evidence on benefits of psychosocial stimulation (PS) and cash transfer programmes in low- and middle-income countries on children's development. We integrated PS into an unconditional cash transfer (UCT) programme for poor Bangladeshi mothers to examine the effects on children's development. METHODS: This cluster randomized controlled trial was conducted in rural Bangladesh from July 2017 to December 2018 in 33 clusters, with 11 clusters randomly assigned to each of the three arms, namely i) PS + UCT ii) UCT-only and iii) Comparison. We enrolled poor mothers and child (6-16 months) dyads eligible to receive maternity allowance by the Government of Bangladesh. Trained local women imparted training to mothers to provide psychosocial stimulation to their children for one year. Children's cognitive, language and motor development were measured with Bayley-III, behaviour with Wolke's ratings and maternal self-esteem with Rosenberg self-esteem scale. The analysis was intention-to-treat. RESULTS: Of the 594 mother-child dyads, 40 (6·8%) were lost to follow-up. Compared to UCT-only, children in the PS + UCT had significant improvement in cognitive (B = 2.96, 95% CI: 0.46-5.47, Effect Size [ES] 0.24SD) and language (2.73, 0.39-5.00, ES 0.21SD) scores and were more responsive to examiner (0.30, 0.06-0.52, ES 0.27SD), while compared to comparison group, they had significantly higher cognitive (3.37, 1.27-6.19, ES 0.32SD), language (2.82, 0.53-5.10, ES 0.24SD) and motor (2.65, 0.24-5.06, ES 0.22SD) scores and were more responsive to examiner (0.30, 0.08-0.52, ES 0.26 SD). The mothers' self-esteem was significantly higher in PS + UCT (2.46, 0.94-3.98, ES 0.48 SD) and UCT-only (1.67, 0.02-3.20, ES 0.32 SD) compared to the comparison group. CONCLUSION: PS integrated into an UCT programme benefited children's neurodevelopment and UCT improved mother's self-esteem. UCT programme may be an important platform for child stimulation programmes for rural poor populations.

Challenges and Solutions Surrounding Environmental Enrichment for Dogs and Cats in a Scientific Environment.

Dogs and cats housed in research-, kennel- and cattery-type settings are reliant on caregivers to optimise their day-to-day experiences and welfare. The goal is to provide enriching environments for physical, social and environmental control; behavioural choice and opportunities to live as varied a life as possible. However, there are numerous challenges in these environments such as lack of appropriate enrichment for group housing, budget for equipment/training, study controls, time and space to make improvements. In addition, research settings are required to comply with legislation for care, husbandry and housing, and as standards differ between regions, conditions will vary between settings. Sharing knowledge in this field can only help drive a wider culture of care by helping improve the lives and welfare of animals cared for. This article presents some of the environmental enrichment strategies effective at the Waltham Petcare Science Institute, UK.

Enriched Environment Procedures for Rodents: Creating a Standardized Protocol for Diverse Enrichment to Improve Consistency across Research Studies.

Exposure to environmental enrichment has beneficial effects on learning and memory, diverse neurobiological effects, and promotes recovery of function after brain injury. The effect of enrichment is produced by a combination of increased social interaction, physical activity, spatial complexity, and novelty. Procedures in the literature have, however, been idiosyncratic with poor consistency in the manner or extent to which protocols provide consistent enrichment. We provide an environmental enrichment protocol that can be easily replicated with minor details determined locally so that animals across cohorts and cages all experience a comparable level of enrichment. Procedures are outlined to generate and use a daily pool of suitably varied objects using a standardized format, with objects systematically varied up to a 40-day continuous period. Together with using a large group of rats in a suitably-sized cage, and regular shifting of the position of food and water and cage location, these procedures have produced robust effects in different laboratories and rat strain, thereby improving comparisons within and across laboratories. Non-enriched comparisons can vary, but typically would include grouped animals in standard laboratory housing without objects and with stable food and water locations. Enrichment is a safe non-pharamacological tool to examine behavioral and neurobiological processes in animal models of the lifespan, brain dysfunction and injury.

Structured physical exercise improves neuropsychiatric symptoms in acute dementia care: a hospital-based RCT.

BACKGROUND: The primary objective of this trial is to investigate the effects of a short-term exercise program on neuropsychiatric signs and symptoms in acute hospital dementia care. METHODS: Within a hospital-based randomized controlled trial, the intervention group conducted a 2-week exercise program with four 20-min exercise sessions on 3 days per week. The control group conducted a social stimulation program. Effects on neuropsychiatric signs and symptoms were measured via the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change, the Neuropsychiatric Inventory, and the Cohen-Mansfield Agitation Inventory. The antipsychotic and sedative dosage was quantified by olanzapine and diazepam equivalents. RESULTS: Eighty-five patients were randomized via minimization to an intervention group (IG) and a control group (CG). Seventy patients (82%) (mean age 80 years, 33 females, mean Mini Mental State Examination score 18.3 points) completed the trial. As compared to the CG (n = 35), the IG (n = 35) showed significantly reduced neuropsychiatric signs and symptoms. Especially, agitated behavior and lability improved. There were no between-group differences concerning antipsychotic and benzodiazepine medication. CONCLUSIONS: This exercise program is easily applicable in hospital dementia care and significantly reduces neuropsychiatric signs and symptoms in patients suffering from predominantly moderate stages of dementia. TRIAL REGISTRATION: German Clinical Trial Register DRKS00006740 . Registered 28 October 2014.

Epigenetic regulation of dorsal raphe GABA(B1a) associated with isolation-induced abnormal responses to social stimulation in mice.

In isolation-reared mice, social encounter stimulation induces locomotor hyperactivity and activation of the dorsal raphe nucleus (DRN), suggesting that dysregulation of dorsal raphe function may be involved in abnormal behaviors. In this study, we examined the involvement of dorsal raphe GABAergic dysregulation in the abnormal behaviors of isolation-reared mice. We also studied an epigenetic mechanism underlying abnormalities of the dorsal raphe GABAergic system. Both mRNA and protein levels of GABA(B1a), a GABA(B) receptor subunit, were increased in the DRN of isolation-reared mice, compared with these levels in group-reared mice. In contrast, mRNA levels for other GABAergic system-related genes (GABA(A) receptor α1, ß2 and γ2 subunits, GABA(B) receptor 1b and 2 subunits, and glutamate decarboxylase 67 and 65) were unchanged. Intra-DRN microinjection of 0.06 nmol baclofen (a GABA(B) receptor agonist) exacerbated encounter-induced hyperactivity and aggressive behavior, while microinjection of 0.3 nmol phaclofen (a GABA(B) receptor antagonist) attenuated encounter-induced hyperactivity and aggressive behavior in isolation-reared mice. Furthermore, microinjection of 0.06 nmol baclofen elicited encounter-induced hyperactivity in group-reared mice. Neither baclofen nor phaclofen affected immobility time in the forced swim test and hyperactivity in a novel environment of isolation reared mice. Bisulfite sequence analyses revealed that the DNA methylation level of the CpG island around the transcription start site (TSS) of GABA(B1a) was decreased in the DRN of isolation-reared mice. Chromatin immunoprecipitation analysis showed that histone H3 was hyperacetylated around the TSS of GABA(B1a) in the DRN of isolation-reared mice. These findings indicate that an increase in dorsal raphe GABA(B1a) expression via epigenetic regulation is associated with abnormal responses to social stimulation such as encounter-induced hyperactivity and aggressive behavior in isolation-reared mice.

Translating the impact of exercise on cognition: methodological issues in animal research.

Physical exercise and fitness have been proposed as potential factors that promote healthy cognitive aging. Some of the support for this hypothesis has come from animal research. Animal studies are also used to propose the physiological mechanisms underlying the cognitive performance improvement associated with exercise. In the present review and meta-analysis, we discuss several methodological problems that limit the contribution of animal studies to the understanding of the putative effects of exercise on cognitive aging. We suggest that the most likely measure to equate exercise intensity in rodent and humans may be oxygen consumption (VO2) because observed values are surprisingly similar in young and older rodents and humans. For practical reasons, several animal studies use young rodents kept in social isolation. We show that social isolation is associated with an enhanced impact of exercise on cognitive performance but not on some physiological measures thought to mediate the effect of exercise. Surprisingly, two months or more of exercise intervention appeared to be ineffective to promote cognitive performance compared to shorter durations. We argue that impact of exercise in socially isolated animals is explained by an alleviation of environmental impoverishment as much as an effect of physical exercise. It is possible that the introduction of exercise in rodents is partly mediated by environmental changes. It may explain why larger effects are observed for the shorter durations of exercise while much smaller effects are found after longer periods of exercise.