In a bad place: Dopamine regulation of contextual fear learning

Learning from experience is essential for survival in animals and humans. Understanding how the brain encodes memory is therefore a significant challenge in biology. The importance of learning and memory to our daily lives is best appreciated by considering people who have various problems with different types of learning and memory. For example, the elderly often start showing mild learning deficits or can suffer from severe impairments in dementias like Alzheimer's disease. On the other hand, sufferers of mental illness can have abnormally persistent memories related to certain events or 'triggers' associated with strong emotions. These range from debilitating fear in anxiety disorders (e.g. post-traumatic stress, panic attacks) to addicts trying to re-live the euphoria experienced during their early 'highs'. The costs of these aging-related and psychiatric conditions to the economy (e.g. NHS, social care, lost workplace productivity) and society (e.g. effects on family and friends) are enormous so there is a real need to better understand the basic biological processes behind learning and memory.

Many brain functions like learning and memory involve communication between different parts of the brain that are inter-connected. Much progress has been made recently in understanding how this 'cross-talk' is involved in various forms of learning, including emotional learning. Lagging behind this progress is our understanding of how certain brain chemicals, or neuromodulators, are involved in regulating brain 'cross-talk' during learning. For example, the neuromodulator dopamine 'tunes' the signals sent between brain cells and is important for emotional learning, but how dopamine affects brain 'cross-talk' during learning is poorly understood.

In this project we will use rats to investigate how dopamine regulates the function of the hippocampus and amygdala, two inter-connected brain areas that are both important for emotional learning, during contextual fear conditioning. In this type of emotional learning, rats are placed in a chamber and then receive mildly painful electric shock. When the rats are later returned to the context they show fear behaviour, even without receiving any shock. This shows that during learning the rats form a representation of the context and associate it with receiving shock, and that this representation and its association with shock are later remembered in that context. The hippocampus encodes the context and sends this information to the amygdala, where it is associated with shock. Previous work has shown that dopamine in the hippocampus is involved in context encoding but whether dopamine in the amygdala is involved in associating the context with shock is unknown.

We recently showed that contextual fear learning is impaired by a dopamine-blocking drug. We will follow up on this by determining if dopamine blockade disrupts 'cross-talk' between the hippocampus and amygdala. To do this we will record electrical activity from these two areas and examine the effects of blocking dopamine on how 'in sync' their activity is during contextual fear learning. We will also determine how dopamine blockade affects the strengthening of connections between brain cells in these two areas. Finally, we will tease apart the effects of blocking dopamine in the hippocampus or amygdala on the separate processes of encoding the context representation and the context-shock association.

This project will lead to a better understanding of healthy brain function involved in learning and memory. This will shed light on the biological factors involved in abnormal learning and memory in aging and in mental illness (e.g. panic induced by returning to the scene of a previous traumatic incident or craving induced by returning to a place where drugs were often used), which will help to identify new leads for developing drug or psychological therapies to treat these conditions better in the future.

Brain functions like associative learning are distributed across inter-connected areas that form neural circuits. Emerging evidence indicates that communication within neural circuits underlies emotional learning but how neural circuit function is regulated by neuromodulators like dopamine remains unclear. We will determine the role of dopamine in modulating hippocampus-amygdala circuit function underlying contextual fear learning in rats.

First, we will determine how dopamine D1-like receptors (D1Rs) regulate communication between the dorsal hippocampus and amygdala by examining their role in modulating the functional coupling of rhythmic oscillations in these areas during contextual fear learning. We will also determine the role of the ventral hippocampus in mediating this functional coupling, given that the dorsal hippocampus and amygdala are connected indirectly through this area.

Next, we will determine how D1Rs regulate synaptic plasticity in this circuit by examining their role in modulating in vivo long-term potentiation in the hippocampus-amygdala pathway. We will also determine how D1Rs regulate amygdala long-term potentiation that is mediated by converging inputs from the hippocampus and somatosensory cortex, which convey representations of the context and the shock, respectively, to the amygdala.

Finally, we will determine if D1Rs in the dorsal hippocampus, ventral hippocampus, and amygdala play dissociable roles in encoding two distinct aspects of contextual fear learning: the contextual representation and the context-shock association.

Determining how dopamine regulates hippocampus-amygdala circuit function during contextual fear learning will enhance our understanding of healthy brain function underlying learning and memory. This will lead to novel insights on brain dysfunction in aging-related learning deficits and in mental illnesses characterized by abnormal associative learning and hippocampus, amygdala, and dopamine dysfunction.

This research will have long-term impact beyond the academic beneficiaries described above by generating new insight on brain dysfunction underlying abnormal learning associated with aging-related conditions and psychiatric diseases. Below we outline the other beneficiaries of our work:

PHARMACEUTICAL INDUSTRY: We will engage with the pharma industry by discussing our results with them at scientific conferences, inviting them as speakers at our workshop and symposia (see Pathways to Impact), and discussing leveraging funding (e.g. LINK grants, CASE PhD studentships) or in-kind contributions (e.g. access to novel drugs) from them to build on this research in the future. We have recently developed links with Boerhinger Ingelheim (BBSRC iCASE studentship 2016-2020) to investigate the neural circuitry underlying cognition and with Eli Lilly on the neurochemical basis of aging-related cognitive decline in relation to our ongoing BBSRC-funded research. We will exploit these links to foster collaborative efforts to follow up on identifying novel targets for cognitive enhancement.

HEALTH CARE PROFESSIONALS: We will engage with local colleagues at the Nottingham University Hospital NHS Trust and the University's Centre for Trauma, Resilience and Growth by inviting them to speak at our workshop (see Pathways to Impact) to discuss the translational relevance of our results for understanding brain dysfunction underlying anxiety disorders like post-traumatic stress.

CHARITIES: We have identified multiple UK-based charities that promote awareness of various health issues that are relevant to this research (see Pathways to Impact). These charities play important roles in advocacy for the aged and mentally ill. We will engage with them by inviting them to promote their work at our outreach events and workshop. As some of these charities fund basic research in our field, we will also discuss leveraging further funding to build on this research. Engaging with these charities will also benefit their end users in the long-term.

UNIVERSITY STUDENTS: Embedding the results of this research in our undergraduate teaching will benefit the students involved. We will include our results in lectures and host summer placement and final year dissertation students to work with the project personnel on this research. Although students are restricted in the work that they can do on in vivo projects, being involved in such work provides invaluable experience to students interested in pursuing a career in this strategically important field. Our PhD students conducting related research will benefit from interacting with the project personnel and from attending meetings where our results are discussed. This also applies to our collaborators' students conducting related computational modeling work (see Letter of Support from Stephen Coombes). Other students affiliated with Neuroscience@Nottingham will also benefit by attending seminars where our results are presented.

SCHOOL STUDENTS: We are active in outreach with local schools. The project personnel will receive outreach training and participate in such activities. These include widening participation schemes, events during Brain Awareness Week (e.g. visiting students in their schools, hosting students at the university) to raise awareness of neuroscience, and promoting understanding of the use of animals in research.

MEMBERS OF THE PUBLIC: We are also active in outreach with the local public. We run a Knowledge Transfer Seminar Series that is open to the public and is aimed at a lay audience. Academics speak on broad issues of general interest in their field and we will give a seminar based on learning and memory, brain function, and mental illness. Adults are also welcome at Brain Awareness Week events (e.g. Brain Matters), which have been very well attended in the past. Our research may also attract interest from the general public through press releases from the University Press Office.