Researchers decode neural pathways of cognitive flexibility across species
Comprehensive analysis reveals how brains generalize learning across species, with implications for neurological disorders
Genomic Press
image:
Neural circuits associated with three cortical regions in cognitive generalization with different manifestations from different species. (A) Emotionrelated brain regions mainly project to PFC and OFC; Sensory-related brain regions mainly project to PPC. (B) PFC, OFC, and PPC show similar brain area distributions from humans, monkeys to rodents.
view moreCredit: Dr. Zhenzhen Quan
BEIJING, China, 20 May 2025 – In a comprehensive Genomic Press review article published today, neuroscientists have unveiled the complex neural mechanisms that enable cognitive generalization—the crucial ability to adapt learning from previous experiences to new scenarios—across different species. The research maps these neural pathways from hippocampus to cortex, providing insights that could potentially transform our understanding of conditions like Alzheimer's disease and autism spectrum disorders.
How Brains Apply Past Knowledge to New Situations
The ability to transfer learning from prior experiences to novel circumstances represents one of the most fundamental aspects of cognitive flexibility and is vital for survival across species. Yet until now, the underlying neural mechanisms that connect different brain regions in rodents, primates, and humans have remained poorly understood.
"Cognitive generalization is essentially how organisms take what they've learned and apply it to new situations," explains Dr. Zhenzhen Quan from Beijing Institute of Technology, corresponding author of the study. "While this mental flexibility enhances survival, the neural architecture supporting it has been something of a black box until recently."
The research team comprehensively analyzed data from numerous studies conducted across rodents, non-human primates, and humans to establish a cohesive framework for understanding how different brain regions contribute to cognitive generalization.
The Hippocampal Foundation of Generalization
The team's findings reveal that the hippocampus plays a critical role in cognitive generalization through two key processes: remapping and replay.
"Our analysis shows that hippocampal remapping activity—where neurons reorganize their firing patterns in response to new environments—creates abstract rules during generalization," notes Dr. Da Song, a co-author of the study. "Different hippocampal subregions handle distinct memory types, allowing for specialized processing of experiences."
The researchers discovered that during sharp-wave ripples, a distinctive brain wave pattern, the hippocampus replays experiences in compressed time sequences. This replay mechanism appears to be fundamental for extracting common features across different experiences, forming the basis for generalization.
Could these hippocampal replay patterns serve as potential biomarkers for early detection of neurodegenerative diseases? The authors suggest this possibility merits further exploration, especially given the disruptions to these patterns observed in conditions like Alzheimer's disease.
Cortical Regions: The Executive Networks of Generalization
The review highlights three critical cortical areas involved in cognitive generalization:
Prefrontal Cortex: Emerges as essential for rule-based categorization across all species studied, processing both low-level and high-level abstractions that allow organisms to identify patterns across diverse experiences.
"The prefrontal cortex demonstrates remarkable consistency across species in its role of abstracting rules from experiences," explains Professor Hong Qing, senior author from Beijing Institute of Technology and Shenzhen MSU-BIT University. "This evolutionary conservation suggests its fundamental importance for cognitive flexibility."
Orbitofrontal Cortex: Drives value-based decision-making and concept-based decisions, helping organisms determine which experiences are worth generalizing based on previously learned outcomes.
Posterior Parietal Cortex: Guides generalization through perceptual processing of past experiences, serving as a sensory history buffer that influences how new perceptions are categorized.
What makes these findings particularly significant is the identification of the integrated neural circuitry connecting these regions. The research demonstrates how similar these brain structures and their associated behaviors are across species, suggesting evolutionary conservation of these critical cognitive mechanisms.
Implications for Neurological Disorders
The team's analysis extends beyond normal brain function to examine how disruptions to cognitive generalization manifest in various neurological conditions.
"Patients with Alzheimer's disease show significant impairment in memory generalization, which correlates with hippocampal volume loss," notes Dr. Quan. "Similarly, individuals with autism spectrum disorder often struggle with rule abstraction and forming prototypical representations, reflecting potential dysfunction in prefrontal processing."
These connections between cognitive generalization deficits and neurological disorders open new avenues for potential diagnostic approaches and therapeutic interventions. Could training that specifically targets generalization processes help mitigate symptoms in these conditions? This remains an intriguing question for future research.
Future Directions
As research technology advances, the authors suggest several promising directions for further investigation, including more detailed mapping of the hippocampal-cortical connections that support generalization and development of therapeutic approaches targeting these networks.
"Understanding the neural foundations of cognitive generalization could lead to novel interventions for conditions where flexibility in thinking is impaired," suggests Professor Qing. "Our next challenge is to translate these insights into practical applications that could benefit patients."
The comprehensive analysis not only clarifies the neural foundations of cognitive generalization but also suggests promising directions for interventions targeting related neurological disorders. By bridging animal models with human studies, the research provides a translational framework that could accelerate development of new therapeutic approaches.
The article in Brain Medicine titled "Neural mechanisms of cognitive generalization across species: From hippocampus to cortex," is freely available via Open Access on 20 May 2025 in Brain Medicine at the following hyperlink: https://doi.org/10.61373/bm025w.0047.
About Brain Medicine: Brain Medicine (ISSN: 2997-2639, online and 2997-2647, print) is a peer-reviewed medical research journal published by Genomic Press, New York. Brain Medicine is a new home for the cross-disciplinary pathway from innovation in fundamental neuroscience to translational initiatives in brain medicine. The journal's scope includes the underlying science, causes, outcomes, treatments, and societal impact of brain disorders, across all clinical disciplines and their interface.
Visit the Genomic Press Virtual Library: https://issues.genomicpress.com/bookcase/gtvov/
Our full website is at: https://genomicpress.kglmeridian.com/
Neural mechanisms of cognitive generalization across species: From hippocampus to cortex
Credit
Dr. Zhenzhen Quan
Journal
Brain Medicine
Method of Research
Literature review
Subject of Research
People
Article Title
Neural mechanisms of cognitive generalization across species: From hippocampus to cortex
Article Publication Date
20-May-2025
Dynamic memory engrams reveal how the brain forms, stores, and updates memories
Recent advances in tracking and manipulating memory traces offer new insights into memory disorders and potential interventions for PTSD
Genomic Press
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Dynamic mechanisms of engram maturation. During the allocation, engram allocation is primarily governed by enhancements in intrinsic neuronal excitability, driven primarily by increased phosphorylation of CREB, which primes these cells for selective recruitment. Following allocation, engram formation is molecularly marked by the expression of IEGs including Fos, Npas4, Arc, and Egr1. The consolidation phase is characterized by epigenetic reprogramming, such as DNA methylation, histone posttranslational modifications (e.g., acetylation, phosphorylation), and histone variant exchange. Concurrently, neuronal excitability is further modulated through synaptic recruitment of NMDA receptors, AMPA receptors, and inwardly rectifying potassium channels (Kir), while dendritic spine density increases to reinforce synaptic connectivity. Throughout this maturation process, engrams transition from a silent state to a functionally mature configuration, marked by enduring structural and molecular adaptations that support long-term memory storage.
view moreCredit: Zhe-Yu Chen
JINAN, Shandong, China, 20 May 2025 – In a comprehensive Genomic Press thought leaders invited review published today, researchers have mapped out the dynamic cellular mechanisms that allow the brain to form, consolidate, generalize, and update memories. This scientific synthesis offers valuable insights into how memories are encoded in the brain and how they can change over time, with substantial implications for conditions like post-traumatic stress disorder (PTSD).
The Hunt for Memory Traces
One of neuroscience's most fundamental questions is how the brain can store, generalize, and update memories. Memories are believed to be stored through biophysical and molecular changes in neuronal ensembles called engrams, distributed across different brain regions. These engrams are sparsely distributed populations of neurons that undergo enduring physical or chemical changes during learning, creating a biological representation of our experiences.
"The search for the mechanistic substrates of memory, what Richard Semon called the 'engram,' has continued into the present day," explains Professor Zhe-Yu Chen from Shandong University, the corresponding author of the review. "Our understanding of memory engrams has evolved from a theoretical abstraction to a biological reality through modern neuroscience techniques."
Neuroscience Breakthroughs Enable Memory Visualization
The review details how recent technological advances have transformed our ability to study memory. Modern techniques now allow scientists to label, track, and even manipulate the specific neurons involved in forming and retrieving memories.
"Advanced methods combining immediate early gene-based tagging with optogenetic manipulation have enabled the identification and control of neuronal ensembles encoding specific memories," notes Dr. Shuai-Wen Teng, co-author of the review. "This technological breakthrough has allowed us to observe memory in action at the cellular level."
Scientists can now visually identify which neurons activate during memory formation and retrieval. More remarkably, they can artificially activate these neurons to induce memory recall, even in the absence of normal sensory cues. This means researchers can effectively "turn on" a memory by stimulating the right cells.
Memory Allocation and Formation
The review explains how neurons are selected to become part of a memory trace during the initial encoding process. This selection isn't random – neurons with higher excitability at the time of learning are more likely to be recruited into the memory ensemble.
"It's like a competition among neurons," Dr. Teng continues. "Cells with elevated baseline excitability exhibit preferential activation during learning and are disproportionately incorporated into memory-encoding ensembles."
This process is regulated by a transcription factor called CREB, which enhances both intrinsic excitability and dendritic spine density. When a neuron has higher CREB activity, it becomes more likely to be recruited into a memory engram.
How Memories Change Over Time
One fascinating aspect of the review covers how memories transform as they consolidate. New memories initially depend on the hippocampus but gradually transition to relying more on the cortex through a process called systems consolidation.
"Following initial synaptic stabilization, memories undergo system consolidation, transitioning from hippocampal dependence to medial prefrontal cortex-dependent storage over days to years," explains Dr. Chen. "This allows hippocampal engrams to retain episodic, context-specific details, while medial prefrontal cortex ensembles encode more schematic, generalized representations."
This natural process explains why memories often become more generalized over time, losing specific details while preserving core concepts. This fundamental brain mechanism supports learning but can also contribute to conditions like PTSD when fear memories become overgeneralized.
Memory Generalization and Anxiety Disorders
The researchers detail how memory generalization, while an adaptive process for applying past learning to new situations, can become maladaptive in conditions like PTSD and anxiety disorders.
The hippocampus plays a crucial role in maintaining memory specificity. When this function is compromised, perhaps due to stress exposure or altered signaling pathways, memories can become overgeneralized, leading to inappropriate fear responses.
"Fear overgeneralization represents a maladaptive behavioral response to nonthreatening stimuli or neutral environments," Dr. Chen explains. "This phenomenon is a hallmark feature of anxiety spectrum disorders such as generalized anxiety disorder, panic disorder, and post-traumatic stress disorder."
The researchers outline several mechanisms that drive memory generalization, including stress-induced changes in hippocampal and amygdala circuits. Understanding these mechanisms could lead to targeted interventions for anxiety disorders.
Memory Updating and Modification
The review also explores how existing memories can be updated with new information. When memories are reactivated, they become temporarily malleable, allowing them to incorporate new data or emotional contexts.
"Memory updating is a fundamental process that allows organisms to adapt to new information, modify existing knowledge, and integrate novel experiences with pre-existing memories," says Dr. Teng. "The valence associated with the hippocampal dentate gyrus memory engram could be bidirectionally reversed."
This suggests exciting possibilities for treating emotional disorders by modifying the emotional associations of traumatic memories. Could therapies be developed that specifically target memory engrams to reduce their emotional impact without erasing the memories themselves? This remains an active area of research with significant clinical potential.
The Future of Memory Research
The review outlines several outstanding questions that researchers are still working to answer. How exactly do nuclear changes during memory formation connect to the reinforcement of specific synaptic connections? What mechanisms drive neurons to join or leave engram networks during different memory processes? How does the brain maintain the delicate balance between memory stability and flexibility?
"Our knowledge of the intrinsic mechanism underlying the offline activation of memory engrams in an unconscious state is totally lacking," notes Dr. Chen. "Understanding how memory representations drift over time depending on our experiences and internal states is a critical area for future investigation."
The article in Brain Medicine titled "Dynamic memory enqrams: Unveiling the celular mechanisms of memory encoding, consolidation, generalizaton, and updating in the brain," is freely available via Open Access on 20 May 2025 in Brain Medicine at the following hyperlink: https://doi.org/10.61373/bm025i.0044.
About Brain Medicine: Brain Medicine (ISSN: 2997-2639, online and 2997-2647, print) is a peer-reviewed medical research journal published by Genomic Press, New York. Brain Medicine is a new home for the cross-disciplinary pathway from innovation in fundamental neuroscience to translational initiatives in brain medicine. The journal's scope includes the underlying science, causes, outcomes, treatments, and societal impact of brain disorders, across all clinical disciplines and their interface.
Visit the Genomic Press Virtual Library: https://issues.genomicpress.com/bookcase/gtvov/
Our full website is at: https://genomicpress.kglmeridian.com/
Dynamic memory enqrams: Unveiling the celular mechanisms of memory encoding, consolidation, generalizaton, and updating in the brain
Credit
Zhe-Yu Chen
Journal
Brain Medicine
Method of Research
Literature review
Subject of Research
Animals
Article Title
Dynamic memory enqrams: Unveiling the celular mechanisms of memory encoding, consolidation, generalizaton, and updating in the brain
Article Publication Date
20-May-2025
