Environmental enrichment and cognitive function across the lifespan

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.

Environmental enrichment induces neuronal elaboration and synaptic strengthening, processes thought to underlie the positive aspects of enrichment on age-related cognitive functioning. Whilst brain derived neurotrophic factor (BDNF) has been repeatedly implicated in the changes associated with enrichment, the molecular mechanisms underpinning its effects are not know. Using a mutant mouse that lacks the kinase activity of mitogen- and stress-activated kinase 1 (MSK1), an enzyme downstream of BDNF/TrkB receptors, and which regulates gene transcription via phosphorylation of CREB and histone H3, we have recently shown that MSK1 is necessary to translate sensory experience into enduring changes in neuronal structure and function: MSK1 kinase-dead mice do not display the increase in hippocampal synaptic transmission observed in wild-type mice and display a blunted increase in spine density. Accordingly, MSK1 plays a pivotal role in translating the activation of BDNF TrkB receptors into the gene expression underlying enduring experience-dependent neuronal plasticity. We now wish to extend these observations to establish the extent to which these MSK1-dependent neuronal adaptations influence learning and memory throughout the life-span by testing wild-type and mutant mice, housed under standard and enriched conditions, in tasks of spatial memory (Barnes and Morris mazes). In addition we will establish, using next generation deep sequencing techniques, the MSK1-dependent genes that are regulated by enrichment and which underpin the enhancement of cognitive function. These studies will provide valuable tangible insight into the molecular mechanisms regulating the influence of enrichment on synaptic structure and function, and the ensuing enhancement of cognitive function. Such studies are a fundamental requirement if we are to develop drugs to slow, halt or even potentially reverse cognitive decline in the elderly.

Who will benefit from this research?
Beyond academic beneficiaries we anticipate a number of stakeholder groups to benefit from our observation that MSK1 regulates the neuronal and cognitive response to environmental enrichment. These include: the pharmaceutical industry, which might consider MSK1 as a novel target for the treatment of age-related and other cognitive impairments; policy makers in government, local authority and health trusts; and patients, carer support groups and charities, in the provision of environmental enrichment and sensory stimulation for pre-term infants, neonatal intensive care units, and suffers of congenital (eg Rett or Down's syndrome), acquired (eg stroke, head injury) or age-related cognitive impairment. The general public will benefit from communications and interactions that will emerge on neuroscience in general and this project in particular.

How will they benefit from this research?
The identification of MSK1 as a prime factor by which environmental influences shape neuronal structure and function to underpin enhanced cognition will herald a novel target for treating age-related and other cognitive impairments: activating MSK1 may provide a stimulus for neuronal elaboration and synaptic function that could be of benefit in delaying, halting or reversing age-related cognitive impairment. In the absence of pharmacological treatments, enriched environments may serve a similar function and could be provided at various care levels from hospital to home. On a broader level, greater insight into how experience shapes neuronal structure and function is of fundamental importance and will provide knowledge into brain development and the influence of the environment. Indeed, analysis of the human MSK1 gene may reveal SNPs as biomarkers for developmental or cognitive phenotypes, which may be of value to large-scale programs such as The Understanding Society initiative, which has two Warwick researchers amongst the team (Profs Weich and Wolke; www.understandingsociety.org.uk). Our work would also underscore the importance of positive rearing in childhood to greater educational and intellectual achievement in later life. The general public, including schools, local charities and support groups, will benefit from opportunities to learn about this research; on the web, in print and in person, which will increase the public knowledge base of the brain and nervous system.

What will be done to ensure that they have the opportunity to benefit from this research?
We will pursue any exploitable IP via the appropriate channels at Warwick. This will act as a conduit to the private sector, whilst protecting our interests. The positive influence of environmental enrichment on brain development will be communicated to health research colleagues at Warwick including in the Dept of Psychology and the Division of Mental Health and Wellbeing in Warwick Medical School. This may translate into local clinical trials of enrichment in neonatal, geriatric and other hospital units, and potentially policy changes related to the findings. Such trials would be brought to the attention of relevant charities and support groups for their input and to alert them of the potential benefit of enhanced sensory stimulation to the development, maintenance, or recovery of cognition. We shall endeavour to broaden understanding of neuroscience through visits, talks and lay literature for the benefit of schools, charities and support groups and the general public. The applicants have a track record in public, private and charity sector engagement. We shall endeavour to increase this level of engagement using direct contact with such groups, and via the appropriate University departments (eg Communications Office, Research Support Services).