Reference:
BB/L00139X/1
Abstract:
The human brain, like other organs, is affected by ageing. This can lead to reduced concentration, forgetfulness, and confusion when confronted with novel or unexpected situations. In more severe cases this puts the person at risk of harm and jeopardises independent living, placing heavy burdens on families and society. There is therefore a great need to both understand the normal brain ageing process, and to develop strategies to limit the impact of ageing on brain function. Environmental influences shape the structure and activity of the mammalian brain. Housing experimental animals in enriched environments in which they have access to toys, exercise and large social groups, results in a number of changes compared to animals kept in standard lab conditions. In particular, age-related decline in learning and memory can not only be delayed, but reversed. At the level of individual brain nerve cells, enrichment causes neurones to be more elaborate, with more processes upon which to receive information from neighbouring neurones, and indeed the strength of this information transfer is greater. These dramatic changes in brain function are not only the preserve of experimental rodents; humans show changes in brain structure and function in response to vocal and musical training, whilst music therapy has had benefits in a variety of patient groups, including the elderly. Unsurprisingly, there is terrific interest in establishing the mechanisms responsible for translating positive environmental influences into greater brain function. Identifying these mechanisms could pave the wave to the creation of targeted cognitive behavioural therapy or “enviro-mimetic” drugs – ie drugs that tap into the molecular mechanisms underpinning the brain’s response to positive sensory experience and nurturing environments. An important prerequisite of tapping into these molecular mechanisms is to identify what they might be. We have identified one such mechanism – an enzyme known as MSK1. MSK1 is activated by a key growth factor in the brain called BDNF, which has been shown to increase in response to enrichment, and is believed to induce the neuronal changes associated with enrichment. Moreover, MSK1 is located in the cell nucleus and regulates gene expression, which would be required to translate sensory experience into long-lasting changes in neuronal structure and function. Using mice that have a mutated, inactive form of MSK1 we have shown that they do not respond to being raised in an enriched environment: the change in the strength of communication between neurones is absent, whilst the changes in the structure of neurones where communication occurs were not as pronounced. The results strongly indicate that MSK1 translates the increase in BDNF seen during environmental enrichment into persistent changes of the type required by the brain to adapt and benefit from experience. In the present proposal we plan to investigate how and when MSK1 regulates the brain’s response to sensory experience and whether these changes translate into improved learning and memory. Importantly, we shall examine the role of MSK1 in older animals to test if MSK1 is needed to maintain cognitive function during ageing and whether environmental enrichment promotes learning and memory in a manner that depends upon MSK1. In addition to these studies on neuronal structure and function and behaviour, we shall also examine the genes that are regulated by MSK1 during enrichment. This will reveal the targets of MSK1 that are necessary to translate environmental and sensory experiences into long-lasting modifications of brain structure and function. Identifying MSK1 as a prime coordinator of the brain’s response to its environment may pave the way for drugs that activate MSK1 with a view to halt or even reverse the decline in brain capacity associated with a variety of causes, including ageing.
PROJECT DETAILS
beginning: 2013.
end: 2016.
Country of research: United Kingdom
Counry of funding source: United Kingdom
Funding organization: Biotechnology and Biological Sciences Research Council
Financing: NATIONAL FUNDINGS – 710 091 €