The human brain has the extraordinary ability to rapidly discern a stranger from someone familiar, even as it can simultaneously remember details about someone across decades of encounters. Now, in mouse studies, scientists at Columbia’s Zuckerman Institute have revealed how the brain elegantly performs both tasks.

“These findings are the first evidence that a single population of neurons can use different codes to represent novel and familiar individuals,” said co-corresponding author Stefano Fusi, PhD, professor of neuroscience at Columbia’s Vagelos College of Physicians and Surgeons, a principal investigator at Columbia’s Zuckerman Institute and a member of Columbia’s Center for Theoretical Neuroscience.

In a paper published today in Neuron , Columbia scientists explored social memory, the ability to remember encounters with others. This form of memory consists of two distinct mental processes-;distinguishing novel and familiar individuals, and recalling details about those who are recognized. We can readily determine whether someone is familiar but may have difficulty in recollecting the details of where and how we know that individual, especially when encountered out of context.” Steven A. Siegelbaum, PhD, co-corresponding author, Chair of the Department of Neuroscience at Columbia’s Vagelos College of Physicians and Surgeons Prior work found it difficult to pinpoint how the brain performs both tasks, given their conflicting demands. The ability to detect whether somebody is familiar or not has to apply across many different locations and events, while recollection involves remembering many specific experiences regarding a given individual.

In the new study, the scientists investigated a brain area called CA2, part of the hippocampus, a pair of seahorse-shaped brain structures essential for memory. Dr. Siegelbaum previously made the groundbreaking discovery that CA2 neurons are specifically important for social memory.

The researchers analyzed the brains of mice using calcium imaging, a technique that relies on genetically altered cells-;in this case, in CA2-;that rapidly change color when active. Calcium imaging enabled Lara Boyle, a former MD-PhD student in the Siegelbaum lab and co-first author of the study, to precisely know which neurons they were examining.

“This helped clear up uncertainty from previous research when it came to distinguishing the mouse brain’s responses to novel and familiar individuals,” said Dr. Siegelbaum, the Gerald D. Fischbach, MD, Professor of Neuroscience and of Pharmacology, and a principal investigator at the Zuckerman Institute.

The scientists first recorded how the rodents’ CA2 cells reacted when they were exposed either to a pair of strangers or a pair of familiar littermates. They next used computational methods, led by Dr. Fusi’s team, to analyze the pattern of activity in roughly 400 to 600 neurons in CA2.

The scientists found the same population of neurons encoded memories of both familiar and unfamiliar individuals. Unexpectedly, the neurons used different patterns of activity depending on a mouse’s level of familiarity with another rodent.

When mice were exposed to other mice that were unknown to them, the resulting activity in CA2 was relatively simple or, in the scientists’ parlance, “low-dimensional.” It’s as if several members of an orchestra played the exact same notes, explained Dr. Fusi. In contrast, exposure to familiar littermates led to more complex, high-dimensional CA2 activity, as if the musicians all played different melodies.

The calculations and the simulations of the researchers suggest that the more complex, or higher-dimensional, neural activity can help the brain encode the detailed memories of past encounters with familiar individuals. In contrast, the simpler, or lower-dimensional activity can help the brain reliably identify novel individuals across different contexts.

“When you encounter someone new, you may use abstract categories to describe them in your head-;for instance, that’s a child, with brown hair, red backpack,” said postdoctoral research associate Lorenzo Posani, PhD, a co-first author on the study who led the computational analysis. “Then, as you get to know them, they become a specific person and personality.”

This fundamental discovery regarding the way in which details about others are encoded may shed light on disorders affecting memory.

“When we look at different mouse models of human diseases like schizophrenia or Alzheimer’s that are known to affect memory, we now can ask more precisely how the neural activity supporting familiarity detection and recollection might be altered,” Dr. Siegelbaum said. “Our hope is that what we have learned may lead to a better understanding of the types of interventions that can rescue memory deficits in those disorders.”

The paper, “Tuned geometries of hippocampal representations meet the computational demands of social memory,” was published online in Neuron on TK, 2024.

The full list of authors includes Lara M. Boyle, Lorenzo Posani, Sarah Irfan, Steven A. Siegelbaum and Stefano Fusi.

Source:

Columbia University

Journal reference:

Boyle, L. M., et al. (2024) Tuned geometries of hippocampal representations meet the computational demands of social memory. Neuron. doi.org/10.1016/j.neuron.2024.01.021 .

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Representative image. Image Credit: ANI Spatial navigation and memory are essential components of our daily lives. Without these talents, we would struggle to navigate our surroundings and remember previous experiences. However, the neural foundation of spatial memory remains poorly known. A study group directed by Prof. Lukas Kunz, who just joined the University Hospital Bonn (UKB), has discovered fresh information on this knowledge gap. He discovered, along with scientists from New York and Freiburg, that different types of nerve cells become active simultaneously during spatial memory and are coordinated by brain waves (“ripples”). The findings have now been published in the journal Nature Neuroscience.

Associative memory allows different pieces of information are linked together. “In the context of spatial memory, associative memory enables us to remember the locations of certain objects in the spatial environment,” explains Prof. Kunz, research group leader for Cognitive and Translational Neuroscience at the Department of Epileptology at the UKB. He is also a member of the Transdisciplinary Research Area (TRA) “Life & Health” at the University of Bonn. “For example, we can remember where in the house we put our keys”. At older age or in certain diseases such as Alzheimer’s, however, this ability is limited. “It is therefore important to investigate the neuronal basis of different forms of human memory,” said Prof. Kunz. In the long term, this could help develop new therapies for memory impairments.

Nerve cells are active while information is retrieved from memory. To further investigate this phenomenon, the researchers recorded the activity of individual nerve cells in epilepsy patients performing a memory task. “In a virtual world, the participants were asked to remember the locations of different objects,” explains Prof. Kunz. The recordings showed that different types of nerve cells became active during this memory task. Some nerve cells responded to certain objects, while other nerve cells activated in response to certain locations. The scientists observed that interactions between the different types of nerve cells became stronger over time when participants remembered the right object in the right place.

In addition to place and object neurons, the researchers observed hippocampal brain waves (“ripples”) that also occurred during the memory task, presumably playing a crucial role in the formation and retrieval of associative memories. “Ripples could be important for the connection of different types of nerve cells and the formation of complex memories. It will be exciting to further investigate this idea in future studies,” explains Prof. Kunz. It will also be interesting to study how memory performance is modulated when ripples are suppressed or triggered, providing insights into the causal relevance of ripples. Prof. Kunz intends to continue the findings that he gained with his colleagues at Columbia University’s School of Engineering and Applied Science in New York and the University of Freiburg at the University Hospital Bonn.

“The department of epileptology at the UKB is well-known for its excellent brain research. The department has the unique opportunity to record the activity of individual nerve cells in the human brain in the video EEG monitoring unit, which is the heart of every epilepsy center. This provides exciting insights into the functioning of the human brain, which is only possible at a few research centers worldwide,” describes Prof. Kunz. In his interdisciplinary research, he builds on the close exchange with other researchers and medical doctors, which is essential for the development of new research ideas. (ANI)

(This story has not been edited by Devdiscourse staff and is auto-generated from a syndicated feed.)

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Key points

First-of-its-kind research shows how the cerebellum modulates dopamine release within the basal ganglia.

Motivation and addiction are both fueled by dopamine activation in the basal ganglia’s substantia nigra.

Too little dopamine causes Parkinson’s disease. Stimulating the cerebellum may be a new treatment option.

The cerebellum (“little brain”) is tucked underneath the basal ganglia; it sits in the back of the skull below the cerebrum. Source: CLIPAREA l Custom media/Shutterstock

Neuroscientists have unearthed a previously unknown dopamine -driven neural pathway between the cerebellum (Latin for “little brain”) and reward centers in the basal ganglia that appears to fuel both the vigor of motivation and the intensity of addiction . These findings ( Washburn et al., 2024 ) were published on January 25 in Nature Neuroscience . The Cerebellum and Basal Ganglia: Separate but Interconnected

We’ve known for decades that the cerebellum helps to control and coordinate voluntary movements. Fluidity and grace when playing sports or doing everyday things like driving a car rely on the cerebellum’s coordination capacities. Damage to the cerebellum can impair fluid movements and well-timed motor control, often resulting in noticeable discombobulation and jerkiness, as seen in people with cerebellar ataxia. The basal ganglia is a subcortical structure in the midbrain located above the cerebellum and below the cerebral cortex. Source: CLIPAREA l Custom media/Shutterstock

As a completely separate subcortical brain structure, the basal ganglia’s substantia nigra region has traditionally been viewed as the brain’s go-no-go reward center that’s turned “on” by dopamine and turned “off” by a lack thereof. When the substantia nigra is flooded with dopamine, it turbocharges reward-seeking behaviors that often drive addiction and cue-induced relapse . Notably, a lack of dopamine in the substantia nigra is a hallmark of Parkinson’s disease.

Until now, the cerebellum’s muscle-coordinating powers and the basal ganglia’s reward-seeking influence were viewed as separate entities that weren’t directly interconnected or intertwined.

The recent discovery of a direct dopaminergic pathway between these two subcortical brain structures is the first direct evidence that the cerebellum modulates dopamine levels in the basal ganglia, influencing reward processing, movement initiation, and motivational vigorousness. New Discovery: The Cerebellum Controls Dopamine Release

The latest (2024) research by Farzan Nadim and colleagues suggests, for the first time, that the cerebellum modulates the release of dopamine into the basal ganglia’s substantia nigra pars compacta (SNc), a reward processing center involved in habit formation , addiction, motivation, and neurodegenerative diseases that affect voluntary movement, such as Parkinson’s disease.

“We are exploring a direct communication between two major components of our brain’s movement system, which is absent from neuroscience textbooks. These systems are traditionally thought to function independently,” Nadim said in a news release . “This pathway is physiologically functional and potentially affects our behaviors every day.”

This study in mice used state-of-the-art optogenetic activation techniques to hack into monosynaptic bilateral projections from the cerebellum to the substantia nigra that the researchers identified as modulating the release of dopamine in ways that drive reward-seeking behaviors. Stimulating or Suppressing the Cerebellum Affects Motivation and Movement

When the scientists shut down this cerebellum>SNc pathway and blocked dopamine signaling from the cerebellum to the basal ganglia’s substantia nigra using optogenetics, motivation to perform voluntary movements necessary to obtain a reward evaporated.

Conversely, when this dopamine-producing pathway was stimulated, it increased the vigor of mice’s motivation to seek rewards. The cerebellum also seemed to attach a higher value to the reward in real-time, which led to mice intensely pursuing a potentially addictive substance and giving them the dopamine-fueled motivation to do so.

More research is needed. But someday, in humans, shutting down this cerebellum-rooted pathway with targeted medications might mitigate addiction. In terms of daily physical activity, finding drug-free, holistic ways to activate the cerebellum’s dopamine-producing pathway could increase people’s motivation to seek exercise, not avoid it.

Theoretically, stimulating the cerebellum with transcranial magnetic stimulation or other therapeutic techniques could jumpstart dopamine production in the substantia nigra in ways that might help people with Parkinson’s disease. Next Steps: Focus on Parkinson’s Disease Treatment Options

“This pathway seems very important to our vigor of movement and speed of cognitive processes,” Nadim says. “Parkinson’s patients not only suffer from suppression of movement but apathy in some cases. The cerebellum’s location at the back of the brain makes it a much easier target for novel therapeutic techniques.”

After establishing that the cerebellum can directly excite the substantia nigra’s dopamine neurons, the researchers’ next step is to explore how stimulating this pathway and jumpstarting dopamine activity in the basal ganglia might relieve Parkinson’s disease symptoms.

References

Samantha Washburn, Maritza Oñate, Junichi Yoshida, Jorge Vera, Ramakrishnan Bhuvanasundaram, Leila Khatami, Farzan Nadim & Kamran Khodakhah. “The Cerebellum Directly Modulates the Substantia Nigra Dopaminergic Activity.” Nature Neuroscience (First published: January 25, 2024) DOI: 10.1038/s41593-023-01560-9

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Modern technology for recording deep-brain activity involves sharp metal electrodes that penetrate the tissue, causing damage that can compromise the signal and limiting how often they can be used.

A rapidly growing area in materials science and engineering is to fix the problem by designing electrodes that are softer, smaller, and flexible — safer for use inside the delicate tissues of the brain. Just last week, researchers from the University of California, San Diego, reported the development of a thin, flexible electrode that can be inserted deep within the brain and communicate with sensors on the surface.

But what if you could record detailed deep-brain activity without piercing the brain?

A team of researchers (as it happens, also from UC San Diego) have developed a thin, flexible implant that “resides on the brain’s surface” and “can infer neural activity from deeper layers,” said Duygu Kuzum, PhD , a professor of electrical and computer engineering, who led the research.

By combining electrical and optical imaging methods, and artificial intelligence, the researchers used the device — a polymer strip packed with graphene electrodes — to predict deep calcium activity from surface signals, according to a proof-of-concept study published this month in Nature Nanotechnology .

“Almost everything we know about how neurons behave in living brains comes from data collected with either electrophysiology or two-photon imaging,” said neuroscientist Joshua H. Siegle, PhD , of the Allen Institute for Neural Dynamics in Seattle , who not involved in the study. ” Until now, these two methods have rarely been used simultaneously.”

The technology, which has been tested in mice, could help advance our knowledge of how the brain works and may lead to new minimally invasive treatments for neurologic disorders. Multimodal Neurotech: The Power of 2-in-1

Electrical and optical methods for recording brain activity have been crucial in advancing neurophysiologic science, but each technique has its limits. Electrical recordings provide high “temporal resolution”; they reveal when activation is happening, but not really where. Optical imaging, on the other hand, offers high “spatial resolution,” showing which area of the brain is lighting up, but its measurements may not correspond with the activity’s timing.

Research over the past decade has explored how to combine and harness the strengths of both methods. One potential solution is to use electrodes made of transparent materials such as graphene, allowing a clear field of view for a microscope during imaging. Recently, University of Pennsylvania scientists used graphene electrodes to illuminate the neural dynamics of seizures .

But there are challenges. If graphene electrodes are very small — in this case, 20 µm in diameter — they become more resistant to the flow of electricity. Kuzum and colleagues addressed this by adding tiny platinum particles to improve electrical conductivity. Long graphene wires connect electrodes to the circuit board, but defects in graphene can interrupt the signal, so they made each wire with two layers; any defects in one wire could be hidden by the other.

By combining the two methods (microelectrode arrays and two-photon imaging), the researchers could see both when brain activity was happening and where, including in deeper layers. They discovered a correlation between electrical responses on the surface and cellular calcium activity deeper down. The team used these data to create a neural network (a type of artificial intelligence that learns to recognize patterns) that predicts deep calcium activity from surface-level readings.

The tech could help scientists study brain activity “in a way not possible with current single-function tools,” said Luyao Lu, PhD , professor of biomedical engineering at George Washington University in Washington, DC, who was not involved in the study. It could shed light on interactions between vascular and electrical activity, or explain how place cells (neurons in the hippocampus) are so efficient at creating spatial memory.

It could also pave the way for minimally invasive neural prosthetics or targeted treatments for neurologic disorders, the researchers say. Implanting the device would be a “straightforward process” similar to placing electrocorticography grids in patients with epilepsy , said Kuzum.

But first, the team plans to do more studies in animal models before testing the tech in clinical settings, Kuzum added.

Read more at www.medscape.com