Age-associated psychiatric conditions such as depression are thought to be associated, in a significant number of cases, with reduced motivation to engage in effortful activities. This comes as no surprise, since lower levels of motivation also are widely seen in younger people who suffer from depression. In young people, very low motivation is atypical; in older people, it may be part of the normal aging process. If so, is there any way to boost motivation and in so doing reduce its potential contribution to depression and other disorders?

Investigators do not yet understand the brain mechanisms that account for lower motivation in aging individuals. This is the target of research by a team at the Washington University School of Medicine co-led by 2019 BBRF Young Investigator Jordan G. McCall, Ph.D. and Shin-ichiro Imai, M.D., Ph.D.

In a new paper appearing in Molecular Psychiatry, Drs. McCall, Imai, and colleagues report the results of experiments performed in mice that tested the impacts of social isolation and aging on levels of motivation in the animals, and examined brain mechanisms underlying the results at the molecular level.

The mice studied in the experiments were of two types: one, sexually matured heathy young adults, the other old but still healthy individuals. The two groups each were raised under one of two conditions: housed for an extended period with other individuals, or in isolation in their own cages.

One way of studying motivation in rodents is to observe how often and for how long they run on a spinning wheel, an activity they find innately rewarding and engage in without the lure of external rewards such as food or drink. When it was dark, old mice ran on the wheel much less than young mice, a behavior previously observed. In the current experiments, mice living in social isolation ran substantially less during the dark time than animals living with others; this was true in both young and old animals.

The reduction in dark-time running was more pronounced in old mice (40%) than young (27%). At least in part, this is likely a function of physiological factors affecting old mice such as reduced skeletal muscle strength and energy metabolism. Overall, the team interpreted the reduced voluntary running among the old mice to reflect the impacts of both aging and social isolation.

Trying to parse this result, the team tested how much effort the animals were willing to expend to obtain a food reward. In this test, socially isolated young mice, as expected, obtained less food than group-housed controls. Old mice raised in a cage with others obtained less food than group-housed young mice, but an amount very similar to that obtained by the young mice living in isolation. Old mice living in isolation obtained even less food.

While both socially isolated young and old mice sought less frequently to obtain a food reward, the results demonstrated to the team that both social isolation and aging were factors in reduced motivation. They proposed that old mice actually responded less, in relative terms, to the stress of social isolation than young mice, perhaps because of reduced motivation that had previously occurred as a result of the aging process.

Further experiments sought to understand biological mechanisms underlying the observed behavioral results. An extensive literature has previously defined the role of the dopamine neurotransmitter system in regulating reward and motivation via a pathway in the brain that connects the ventral tegmental area (VTA) to limbic structures. Two major dopamine cell populations have been identified in the VTA and the substantia nigra (SN) that locate adjacently in the ventral midbrain. To determine the mechanism for the observed age-associated decline in motivation, the team examined expression levels of characteristic genes in these two regions by collecting tissue samples from young and old animals. This revealed that expression of brain-derived neurotrophic factor (BDNF) was significantly decreased in the VTA of aged mice.

BDNF, as past research by BBRF-funded researchers and others has shown, is a key brain protein essential for neuron growth, survival, and synaptic connection, and plays a critical role in learning, memory, and overall brain function. Low levels of BDNF have been linked to neurodegenerative diseases like Alzheimer's and Parkinson's, as well as mood disorders.

In the team’s current experiments, BDNF expression was significantly reduced throughout the aged VTA, and not only in dopamine neurons. After genetically “knocking down” the expression of BDNF in young mice, the researchers noticed the animals had reduced motivation very similar to that observed in old mice in the behavioral tests. This suggested to them that reduction of the BDNF protein in the VTA contributes to impaired reward-seeking motivation in aged mice.

In past research, BDNF levels in the VTA have been linked with development and progression of impaired reward-seeking and drug addiction. The current experiments further suggest to the team that BDNF also plays an important role in maintaining motivation in normal, healthy individuals, a function that deteriorates as part of the aging process.

In past research the team had shown that specific subpopulations of neurons in two parts of the hypothalamus (a hub that regulates hormones, appetite, sleep and other functions) play vital roles in “counteracting age-associated functional decline and determining longevity in mice.” They are now eager to determine if these same neuronal subpopulations also regulate motivation, via neurons in the VTA that express BDNF. Part of this effort will be to test whether it might be possible to restore reduced motivation in mice by supplementing levels of eNAMPT, an enzyme that counteracts aging.

As for the relevance of this research to people, the team notes that BDNF levels in the human brain are known to decrease with age, and that high BDNF levels have been linked with slower rates of cognitive decline. It has been proposed that BDNF depletion may impair synaptic transmission in the aged brain. The research just reported suggests that declines in BDNF may well be linked with reduced motivation in people as they are in rodents. This potential mechanism of age-associated changes in human motivation and the related findings regarding the importance of BDNF in the VTA, in the team’s view, could “stimulate the development of interventions to keep our motivation levels high and healthy during aging.”