Neural Circuitry and Neurochemical Modulation in Cognitive Function


The hippocampus is primarily known for its role in forming and retrieving memories, particularly spatial and declarative memories. The prefrontal cortex, on the other hand, is crucial for higher cognitive functions such as planning, decision-making, and moderating social behavior. The interaction between these two regions helps integrate past memories with current executive functions, enabling adaptive behaviors. Neuronal synchronization which involves the coordinated firing of neurons across different parts of the brain. For instance, in the hippocampus and the prefrontal cortex, synchronization often occurs through oscillatory brain waves, such as theta and gamma rhythms. These rhythms facilitate the efficient transfer of information and integration of neural activity across distant brain areas. Disruptions in the synchronization between the hippocampus and the PFC have been associated with various mental health disorders including schizophrenia where patients often exhibit disrupted theta and gamma synchrony, which may underlie symptoms such as disorganized thinking and memory impairments. Moreover, depression is thought to have altered connectivity and synchronization between these regions correlating with symptoms such as impaired decision making and persistent negative thoughts. Understanding how synchronization affects mental health can lead to better targeted interventions that address the specific neural circuits involved. This could improve outcomes for treatments of psychiatric conditions, offering hope for more effective management of mental health disorders. To this end, new international collaborative research published in Nature Journal and led by Professor Ueli Rutishauser from the Cedars-Sinai in Los Angeles and conducted by postdoctoral fellow Dr. Jonathan Daume, Dr. Jan Kamiński, Dr. Andrea   Schjetnan, Dr. Yousef Salimpour, Dr. Umais Khan, Dr. Michael Kyzar, Dr. Chrystal   Reed, Dr. William   Anderson, Dr. Taufik   Valiante, & Dr.  Adam   Mamelak, the researchers investigated novel neuroscientific approaches to understanding and manipulating brain function to address neurological disorders. The team utilized a multi-modal approach that combined state-of-the-art techniques in neuroimaging, electrophysiology, and genetic manipulation. Key among these was the use of high-resolution functional MRI (fMRI) alongside intracranial electroencephalography (EEG) recordings. This combination allowed for the precise mapping of neural activity at both the macro and micro levels, providing insights into the interconnected nature of neural networks across different brain regions. Additionally, optogenetics played a crucial role in the project, offering the ability to control the activity of specific neurons with light. This technique was complemented by chemogenetics, which involves the manipulation of neuron activity using chemically engineered receptors that can be activated by designer drugs. These methods were pivotal in deciphering the causal relationships between neural circuit functionality and behavioral outcomes.

The researchers found significant evidence of neural synchronization between the hippocampus and the prefrontal cortex during tasks requiring complex decision-making and memory integration. This synchronization appeared essential for the consolidation of new memories and the retrieval of existing ones. The experiments also highlighted the role of dopamine and serotonin in modulating the strength of neural connections. For instance, increased dopamine levels were associated with improved performance on tasks requiring working memory and cognitive flexibility, while serotonin appeared to stabilize mood and anxiety levels, affecting decision-making processes. Through optogenetic and chemogenetic manipulation, researchers established direct causal relationships between specific neural circuits and behavioral outputs. For example, activation of certain pathways in the hippocampus directly enhanced memory retention, whereas inhibition of the same pathways impaired memory. The study also found differences in brain activity patterns between normal and pathological states. In patients with neurological disorders, there were marked disruptions in the typical patterns of neural activity and connectivity, which correlated with their cognitive deficits. Therapeutic Potential: The findings demonstrated potential therapeutic targets for neuromodulation techniques. By adjusting the activity of specific neural circuits, it might be possible to alleviate symptoms or even reverse some of the cognitive deficits associated with neurological diseases.

The study is significant because the research team provided profound insights into the neural circuitry underlying complex cognitive functions such as memory, learning, and decision-making. By mapping the interactions between different brain regions like the hippocampus and prefrontal cortex, they helped elucidate how these areas work together to support higher cognitive functions.  Moreover, they successfully identified the roles of neurotransmitters like dopamine and serotonin in modulating neural connections, which contributes to the foundational knowledge necessary for developing targeted treatments for mental health disorders. This is particularly relevant for conditions characterized by neurotransmitter dysregulation, such as depression and schizophrenia.  Furthermore, the detailed mapping and manipulation of neural circuits provide a basis for developing new therapeutic approaches that could potentially correct dysfunctions in specific neural pathways. This could lead to innovative treatments that are more effective and have fewer side effects than current options. Additionally, understanding the variability in neural mechanisms across different populations aids in the push towards personalized medicine, where treatments can be tailored to the unique neurological profiles of individual patients.

Despite these advancements, the study also underscores several challenges in the field. One significant issue is the translational gap between animal models and human applications. Many of the techniques used, such as optogenetics, are not yet applicable to human subjects in clinical settings due to ethical and technical barriers.  Overall, the experiments conducted by the team led by Professor Ueli Rutishauser have significantly advanced our understanding of the neural mechanisms that underlie cognitive functions and have laid the groundwork for developing targeted interventions for neurological and psychiatric conditions. The detailed understanding of how neural circuits interact and are modulated opens new avenues for the treatment of complex brain disorders.

Neural Circuitry and Neurochemical Modulation in Cognitive Function - Medicine Innovates

About the author

Professor Ueli Rutishauser

Cedars-Sinai, Neurosurgery

The laboratory of Ueli Rutishauser, PhD, is investigating the neural mechanisms of learning, memory, and decision making. We are a systems neuroscience laboratory and use a combination of in-vivo single-unit electrophysiology in humans, intracranial electrocorticography, eye tracking, behavior, and computational approaches. An overarching goal is to capitalize on special neurosurgical situations to advance knowledge of the human nervous system. We have helped pioneer the technique of human single-neuron recordings and continue to advance the tools, methods and surgical techniques that allow such experiments. Recent work has focused on the neural mechanisms of episodic memory and single-trial learning, the representation of novelty and familiarity in the human hippocampus, amygdala and basal ganglia, the theta rhythm, the mechanisms of metacognition such as error monitoring, and the neural representation of faces and emotions.

About the author

Jonathan Daume, PhD

Postdoctoral Fellow

Jonathan Daume, PhD, received his doctorate in Cognitive Neuroscience from the University Hamburg in Germany. He is currently a Leopoldina Academy of Sciences Postdoctoral Fellow at Cedars-Sinai Medical Center.


Daume J, Kamiński J, Schjetnan AGP, Salimpour Y, Khan U, Kyzar M, Reed CM, Anderson WS, Valiante TA, Mamelak AN, Rutishauser U. Control of working memory by phase-amplitude coupling of human hippocampal neurons. Nature. 2024 Apr 17. doi: 10.1038/s41586-024-07309-z.

Go To Nature.