A09
The mammillary body (MB) is one of the hippocampus’ main projection targets and plays a major role in the processing of episodic memories. In the early stages of Alzheimer’s disease, hippocampal function deteriorates while the MB remains relatively unaffected. Project A09 aims to unlock potential reserve mechanisms in the MB to improve memory processing in the diseased brain. We already pioneered single-cell in vivo calcium imaging to understand MB mnemonic coding properties. We will use neural activity manipulations to enhance hippocampus–MB functional connectivity.
Principal Investigators
Dr. Oliver Barnstedt
Dr. Anne Petzold
Co-Workers
Carolin Schumacher
Te-Wei Su
Melika Kashi Zenuzi
Memories and dementia
Our memories form the story of our life – be it our first time riding a bike, the school graduation ceremony, or yesterday’s football match. The incidence of profound and progressive memory loss – dementias – is rising. In the coming decades, up to 150 million people worldwide will suffer from some form of dementia. To stem this surge, we need to identify therapeutic interventions to treat and – at best – prevent dementia. To build a foundation for the development of therapeutic strategies, scientists worldwide are working to identify the building blocks of memory.
The mysterious mammillary body
The cornerstone of the brain’s memory system is the hippocampus. It is also the brain structure that degenerates first in dementia patients and produces profound memory loss in the course of disease. For us to store and remember memories, the hippocampus needs to communicate with the rest of the brain. One of the main communication partners of the hippocampus is the mammillary body (MB), two small marbles at the underside of the brain. When the MB is damaged – due to alcohol dementia, for example – patients have great difficulties remembering the past and making memories of the present. Yet, despite a century of research, the precise role of the MB in memory remains enigmatic.
The goals of our project
Our project aims to understand the role the MB plays in memory formation: is the MB important for storing new memories or for remembering past ones, or both? Are all neurons in the MB the same or do they fulfil different memory functions? Does the MB suffer from dementias – such as Alzheimer’s disease – and how? Ultimately, we want to gain control over MB neurons to alleviate memory loss in dementia patients.
Memories in the mammillary body
When memories are formed, the networks of neurons in the hippocampus and its communication partners reorganise. The process of organising and reorganising the connections between neurons in the wake of an experience is called neural plasticity. Previous research suggests that the MB exhibits extensive plastic changes during the formation of memories. As a first step, we will use fluorescent labelling strategies to mark memory traces in the MB of rodent brains. As a second step, we will teach rodents to remember different spatial locations baited with treats. Then, we will turn the activity of MB neurons on and off using novel optogenetic tools to test how much the animals rely on these neurons to remember the location of the treats.
Dynamic memory coding in the mammillary body
When we mark memory traces in the MB with fluorescent labelling techniques, we get one picture of the memory trace at a time – a snapshot. But what are the activity patterns when animals – or humans – explore and form memories of their environment? To “see” the activity of those neurons live, while memories are being stored in the brain, we will use advanced microendoscopy (single- and two-photon calcium imaging) that provides us with a direct window into the brain’s MB. We will use this information to build models of how MB neurons help us store memories.
How does Alzheimer’s disease affect mammillary body structure and function?
Patients with Alzheimer’s disease suffer from severe memory loss that gets worse and worse as the disease progresses. Scientists and doctors observed that the progression of Alzheimer’s disease goes hand in hand with hippocampal cell death. At this point, it is not clear whether cells also die in the MB, and whether such cell death plays a role in the memory loss of Alzheimer’s patients. Now, we will systematically investigate how Alzheimer’s disease impacts MB structure and function.
Can we rescue memory deficits in AD through stimulation?
If the cells of the MB stay relatively intact in Alzheimer’s disease, there is hope that MB neurons may support or overtake some functions of the degenerating hippocampus. We will test this possibility experimentally: we will develop protocols to stimulate the MB in healthy and diseased brains of an Alzheimer’s disease model. We hypothesise that such stimulation may overcome disease-related weakened hippocampal inputs and may restore healthy memory function. To test this hypothesis, we will test whether such stimulation helps animals to remember the location of treats, essentially testing the MB’s potential as a neural resource.
A glimpse into the future
We aim to uncover the role of an important brain region of the memory system – the mammillary body – for making memories and retrieving them and test its resilience to Alzheimer’s disease. This research will lay the foundation to explore the potential of the mammillary body as a neural resource to improve memory function. Since deep brain stimulation can be taken to the clinic to improve brain function – such as deep brain stimulation of dopamine neurons in Parkinson patients – our research of the memory functions of the mammillary body will contribute to the development of new therapies for dementias such as Alzheimer’s disease.