Environmental enrichment and cognitive function across the lifespan

Lead Research Organisation: University of Warwick
Department Name: School of Life Sciences

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.

Technical Summary

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.

Planned Impact

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).
 
Description That the enzyme MSK1 plays an important role in the synaptic and cognitive changes associated with environmental enrichment
Exploitation Route We wish to establish whether other forms of cognitive enhancement operate through MSK1. This might lead to the development of drugs that target this system for the remediation of a number of congenital, acquired and age-related forms of cognitive declien.
Sectors Communities and Social Services/Policy,Education,Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description NC3Rs Expert panel on refinement in animal models of epilepsy
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guideline committee
Impact Description of best practice and welfare recommendations in the use of animals to study epilepsy
 
Description Additional Behavioural Equipment for BBSRC EE grant
Amount £7,000 (GBP)
Organisation Sylvia Waddilove Foundation 
Sector Charity/Non Profit
Country Unknown
Start 06/2014 
End 05/2015
 
Description Top up funds for BBSRC Environmental Enrichment grant
Amount £30,000 (GBP)
Organisation The WPH Chartable Trust 
Sector Charity/Non Profit
Country Unknown
Start 01/2014 
End 01/2017
 
Description Provision of mutant mice and signalling expertise and reagents 
Organisation University of Dundee
Country United Kingdom 
Sector Academic/University 
PI Contribution we provide the neurobiological context and analysis for the work of our collaborators
Collaborator Contribution our collaborators make mice relevant to the study of gene transcription
Impact 2 publications already, 2 manuscripts under consideration
Start Year 2006
 
Description Animal Welfare Research Network presentation 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Invited presentation on the influence of environmental enrichment on cognition in rodents as part of the BBSRC-supported Animal Welfare Research Network 2nd Annual Meeting, Birmingham March 2017 - Neuroscience and Animal Welfare Techniques Session
Year(s) Of Engagement Activity 2017
URL http://awrn.co.uk/
 
Description Aspiring Professionals session at local School 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact round-table career discussion with Year 12 students at local school
Year(s) Of Engagement Activity 2017
URL http://www2.warwick.ac.uk/fac/sci/lifesci/research/bfrenguelli/pes/
 
Description Brain Awareness week activity in local museum 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact BF took part in a Brain Awareness Week activity in a local museum where we had
brain models, Golgi sections and microscopes available to the public, as well as neuro-related
colouring in for younger visitors.
Year(s) Of Engagement Activity 2015,2016
URL http://www2.warwick.ac.uk/fac/sci/lifesci/research/bfrenguelli/pes/
 
Description Brain research display at a local museum 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact a Brain Awareness Week activity in a local museum (Herbert, Coventry) where we had brain models, Golgi sections and microscopes available to the public, a reaction time and nerve stimulation demonstration, as well as neuro-related colouring in for younger visitors.
Year(s) Of Engagement Activity 2017
URL http://www2.warwick.ac.uk/fac/sci/lifesci/research/bfrenguelli/pes/
 
Description Career Bites session at local school 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Career talk for year 10 and 11 students at a local school describing career path and options for students studying sciences at University
Year(s) Of Engagement Activity 2017
URL http://www2.warwick.ac.uk/fac/sci/lifesci/research/bfrenguelli/pes/
 
Description Career talk at local school 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact career talk to local school students
Year(s) Of Engagement Activity 2018
 
Description Careers session at local school 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Talk at a local school about career in science
Year(s) Of Engagement Activity 2017
 
Description Careers talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact discussion with school students about careers in science
Year(s) Of Engagement Activity 2018
 
Description Careers talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact BF has signed up with a local school, where he has spoken several times previously, to talk to
students about careers in science and research and gave such talks in 2015, 2016 and 2017
Year(s) Of Engagement Activity 2015,2016,2017
URL http://www2.warwick.ac.uk/fac/sci/lifesci/research/bfrenguelli/pes/
 
Description Evening for the general public on the ageing brain 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact An evening of talks and discussion on the concept of longevity, health ageing and the ageing brain
Year(s) Of Engagement Activity 2018
 
Description Participation in a Warwick university Science Fair 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Multi STEM subject activity evening primarily for local school children and their parents/carers featuring many talks, tours, exhibits and demonstrations.
Estimated ~600 visitors
Year(s) Of Engagement Activity 2017
URL http://www2.warwick.ac.uk/fac/cross_fac/xmas/impact/xmas_scientist_experience_2016/xmas_science_gala...
 
Description Public engagement at the Hive, Worcester 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Participation of BBSRC-funded PDRA, Dr Lorenzo More at two events at The Hive in Worcester in 2016 and 2017 "Taking a closer look at the brain" as part of British Science Week
Year(s) Of Engagement Activity 2016,2017
URL http://www.thehiveworcester.org/
 
Description Talk to A Level students 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact participation in a day of science talks to 6th formers - gave seminar on cognitive enhancement
Year(s) Of Engagement Activity 2018
 
Description Talk to A level students on cognitive enhancers 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact BF spoke on the enhancement of cognition at Think Science, an event organised by Warwick
University chemistry and biology students and aimed at A-level students in the Midlands.
Year(s) Of Engagement Activity 2015,2016
URL http://www2.warwick.ac.uk/fac/sci/lifesci/research/bfrenguelli/pes/
 
Description The Coventry Elephantastic 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact large numbers of general public attended this PE brain awareness event in a local library
Year(s) Of Engagement Activity 2017
URL https://warwick.ac.uk/about/community/publicengagement/support/public-engagement-at-warwick/elephant...
 
Description The Healthy Brain Science Evening 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Evening describing neuroscience research at Warwick focusing on healthy brain ageing and lifestyle
Year(s) Of Engagement Activity 2016
 
Description Work experience for school students 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact exposure to neuroscience research
Year(s) Of Engagement Activity 2017
 
Description careers talk at local school 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact discussion with school students about careers in science
Year(s) Of Engagement Activity 2018
 
Description participation in a Science Gala 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Had an exhibit on neuroscience at a Science Gala; very well attended
Year(s) Of Engagement Activity 2019
URL https://warwick.ac.uk/fac/cross_fac/xmas/impact/news/?newsItem=8a1785d86850d8d90168b92eb4b74d46
 
Description participation in a public engagement event on epi/genetics and behaviour 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact discussed importance of upbringing in influencing the epigenome and behaviour
Year(s) Of Engagement Activity 2018
 
Description quote in New Scientist on epilepsy research 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact quote in New Scientist re stems cells in epilepsy
Year(s) Of Engagement Activity 2018
URL https://www.newscientist.com/article/2188510-stem-cells-implanted-into-the-brain-stop-epilepsy-seizu...
 
Description quote in iNews on epilepsy research 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Gave opinion on
Year(s) Of Engagement Activity 2018
URL https://inews.co.uk/news/health/why-a-chemical-found-in-worms-could-hold-the-key-to-reducing-epilept...
 
Description research lab work experience 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact The lab hosted work experience students from local Secondary Schools and has arranged
for a group of students to visit the Department via the School of Life Sciences Outreach Po
Year(s) Of Engagement Activity 2015,2016
URL http://www2.warwick.ac.uk/fac/sci/lifesci/research/bfrenguelli/pes/
 
Description video interview on cognitive enhancers 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Schools
Results and Impact BF gave a video interview on movie depictions of cognitive enhancement for Warwick's IGGY
program "A no-fee global educational social network designed to help gifted and talented young
people aged 13-18 realise their full potential."
Year(s) Of Engagement Activity 2015