While finding answers has never been easy, doing so could help many people with psychiatric or neurological conditions, Institute Director Li-Huei Tsai said in her opening remarks.
“The essential questions is this field arise at every scale from molecular and cellular to systems to computation and behavior,” Tsai said. “The importance of these questions is equally urgent for advancing fundamental science and clinical application.”
The fount of flexibility
The ability of the brain to change and adapt with experience, a flexibility that neuroscientists call “plasticity,” begins with the connections, or “synapses,” that neurons form with each other. In her talk Picower Institute Professor Elly Nedivi described how her research group literally watches plasticity happen by individually labeling different types of synapses under the microscope and tracking how they come and go on a daily basis as a mouse has experiences. The research has enabled her to see how neurons try out new connections to later be discarded or cemented, and how cells appear to fleetingly form inhibitory synapses next to permanent excitatory ones perhaps as a way of taking them offline when needed.
To understand the basis of cognitive flexibility, Yale Professor Jessica Cardin, a former Picower Institute postdoc, is looking at the broader scale of brain-wide circuits.
“If you had to have a specialist circuit for every single potential experience you could have across your entire lifetime your brain would be the size of a large truck,” she quipped. “You don’t have specialist circuits, you have a lot of generalist circuits especially in the cortex where the neurons in both local and large scale circuits adapt almost instantaneously to changes in the ongoing onslaught of sensory inputs as well as changes in your cognitive and behavioral context.”
In her research, for instance she has tracked how an animal’s behavioral state – highly aroused or calm – varies the ability of neurons in circuits of the visual cortex to encode information and showed how a particular neuron type, called “VIP,” helps to regulate this state dependence and is also associated with widespread activation of circuits across the cortex. With this new knowledge and tools to image circuit activity across the cortex, she has also been studying how the cortical circuits of cognitive flexibility differ in mice engineered to harbor autism-associated genes.
To flexibly control attention, the cortex engages in a dialogue with a deeper brain region called the thalamus, explained Michael Halassa, an assistant professor in MIT’s Brain and Cognitive Sciences Department, member of the McGovern Institute for Brain Research and affiliate member of the Picower Institute. His research to model that interaction suggests that based on a cognitive goal, for instance to pay attention to one thing vs. others, different sets of neurons in a region called the mediodorsal thalamus respectively influence the coordination of prefrontal neurons and help configure prefrontal circuits to inhibit sensory inputs that would compete with the stimulus of interest. Halassa, a psychiatrist, noted that these mechanisms might be implicated in some of the cognitive aberrations evident in autism or schizophrenia.
Novel ideas about memory
Interregional relationships also help endow memory with meaning. The hypothalamus, for instance, helps the hippocampus integrate different dimensions of novelty with memories, said Thomas McHugh, a Professor at the RIKEN Center for Brain Science in Japan who was one of the earliest faculty members of the Picower Institute.
“Novelty can come in many different forms,” he noted. When he returns to Kendall Square he sees the novel spatial context of new buildings, but he also encounters the novel social context of new people around the Institute. In recent research, his team has been able to track how cells in the supramammillary nucleus of the hypothalamus convey these different kinds of novelty via circuit connections with the separate parts of the hippocampus that integrate that kind of information in representing memory.
While McHugh highlighted the integral importance novelty has for memory, Martin Furhmann, a group leader at the German Center for Neurodegenerative Diseases, described a way in which misregulation of the intersection between the two in Alzheimer’s disease may present a conflict. In his research, mice genetically engineered to model Alzheimer’s disease stored and encoded memories in ensembles of hippocampus neurons just like healthy mice did. But then he found they later had trouble recalling those memories. He traced that trouble in the disease model to potential interference by an overlapping ensemble of neurons encoding novelty. Artificially suppressing those interfering neurons, he said, improved memory recall.
One of the most fundamental and important uses of memory is navigation, two speakers noted. Multiple times a day we need to find our way somewhere to get what we need, whether it’s finding our car in a parking lot or making our way to a restaurant to eat. While most of us can take that for granted, Professors Christopher Harvey of Harvard University and Lisa Giocomo of Stanford University are dedicated to dissecting how we do that.
Harvey described a model of how several regions of the cortex combine to take in sensory information, such as the environment an animal is moving through, factor that into a plan for how to move, and then send that information off to other parts of the brain to effect that motion. It’s unsurprising that the visual cortex does that first job, but more novel are findings that the retrosplinial cortex is an apparent locus of making choices and planning and the locomotor signals are concentrated in anterior regions of the posterior parietal cortex.
Giocomo, meanwhile, focused on a separate part of the cortex, the medial entorhinal cortex, whose specialty is not only making maps of environments, but also tracking speed, direction and where the borders of a space are. In her talk she showed that these cells actually maintain multiple maps in which they can account for changing conditions, both in the environment and in behavior. When mice learned the location of a reward within an environment, she found, medial entorhinal cortex neurons restructured their mappings to account for it, providing a means for dynamically remapping spaces to account for different contexts.
Giocomo’s studies required recording from hundreds of neurons, feat that is difficult to achieve but essential for extracting richer information about the activity of cells in neural circuits. Speaker Andreas Schaefer of the Francis Crick Institute in London reported his progress in attempting to create sensors that could track the electrical activity of neurons by the thousands. His strategy has been refine the manufacture of very long thin, well insulated wires, to develop ways of spacing them apart so they don’t damage tissue when inserted, and then reliably connecting them to a computer chip to extract the information for analysis.
Modeling the mind
The ability to formulate these questions, much less invent and employ sophisticated technologies to answer them, is unique to humans. In the symposium keynote talk, Mu-ming Poo of the Institute of Neuroscience in Shanghai argued that to understand how that intelligence evolved and what neural substrates enable it, scientists should continue to find ways to study that in non-human primates, which can model higher-level cognition in ways that rodents cannot. Moreover, he said, non-human primates can provide better models of disease affecting cognition, including psychiatric conditions such as autism. In his talk he described his efforts to study self-awareness in rhesus macaques and to develop genetic models of disease in cloned animals.
Poo readily acknowledged that there is an ethical debate among people who have different opinions on whether and how such research should advance. He said his goal is to develop new therapies and better understand cognition.
In closing the day, Picower Institute Associate Director Matt Wilson said such questions often arise when a field is at its frontier.
“This has really been really remarkable to be going from synapses to circuits to systems and the incredible sophistication and combination of tools involved,” he said. “There are a whole host of issues and questions about how we can apply this science and where the science is going.”