Memory Formation + Selection

Recent research from Rockefeller University, published online in Nature on November 26, 2025 offers a substantially expanded view of how the brain determines which experiences become long-term memories. Long-term memories are those that persist for days, months, or years. While neuroscientists have long understood that only a fraction of moment-to-moment experience is preserved, the new work reveals the biological decision mechanisms that govern whether a newly formed memory trace is stabilized, modified, or allowed to decay. Central to this framework is the concept of a consolidation window, the period after learning during which a memory remains sensitive to reinforcement or erosion. The consolidation window is the time after an experience when neural circuits can strengthen or weaken the memory. The Rockefeller study shows that memory selection within this window is regulated by a coordinated sequence of neuronal activity patterns, neuromodulatory input, and transcriptional programs whose timing determines the ultimate persistence of the memory. Neuronal activity patterns are the specific sequences in which neurons fire to encode information. Neuromodulatory input refers to chemical messengers, such as dopamine or norepinephrine, that adjust how strongly neurons respond.

Memory formation relies on a distributed network rather than any single brain structure. The hippocampus is essential for encoding new episodic and spatial memories, acting as a binding hub that links the elements of an experience. Episodic memories are memories of personal experiences, and spatial memories involve the locations and contexts of events. The amygdala assigns emotional significance to events and biases consolidation when threat, reward, or novelty are present. Novelty refers to stimuli that are new or unexpected and attract attention. The cerebellum contributes to procedural learning and conditioned motor responses. Procedural learning involves acquiring skills and habits, and conditioned motor responses are reflex-like actions learned through repeated experience. These systems interact continuously, and emotionally important experiences recruit stronger neuromodulatory support, amplifying synaptic plasticity associated with consolidation. Synaptic plasticity is the ability of connections between neurons, called synapses, to change in strength. In the new Rockefeller paradigm, however, the critical discovery is that a thalamocortical circuit, rather than the amygdala or hippocampus alone, plays a decisive role in gating memory stabilization. Thalamocortical circuits are pathways connecting the thalamus, a brain region that relays sensory and motor information, with cortical areas of the brain. Specifically, communication between thalamic nuclei and the anterior cingulate cortex (ACC) was shown to regulate whether a memory becomes long-lasting. The ACC is a region of the cerebral cortex involved in decision-making, emotion, and attention.

Earlier models suggested that consolidation occurred mainly within a few hours after learning. More recent work has shown that consolidation often continues over 24 to 48 hours. Factors such as sleep and circadian state may modulate this process, although these were not directly manipulated in the Rockefeller study. Circadian state refers to the phase of the internal biological clock relative to the day-night cycle. Rodent behavioral research already demonstrated that synaptic and molecular changes can unfold over multiple days, but the Rockefeller findings provide a mechanistic explanation: memory-supporting transcriptional programs appear in distinct phases, each acting as a molecular “timer.” Molecular timers are sequences of gene activity that act at defined times to influence memory persistence. These programs, discovered in a mouse virtual-reality learning paradigm, involve sequential transcriptional regulators—CAMTA1 and TCF4 activity emerging early in thalamic neurons, followed by ASH1L activity in the ACC at later stages. Each factor was shown through time-specific CRISPR perturbations to be necessary only during its respective window, indicating that memory maintenance depends on a temporally ordered cascade rather than a single prolonged mechanism. CRISPR perturbations are targeted genetic modifications that temporarily or permanently alter gene function.

Long-term memory storage also requires systems consolidation, a gradual reorganization of memory across brain regions that occurs over weeks, months, or years. During this process, memories that initially depend heavily on the hippocampus become represented within distributed cortical networks, which support more stable and generalized retrieval. Distributed cortical networks are interconnected regions of the cerebral cortex that collectively encode and integrate information. Systems consolidation primarily shapes explicit or declarative memories—those involving consciously accessible facts and events. Declarative memories are memories that can be consciously described. Implicit or non-declarative memories, such as habits, skills, and conditioned emotional responses, depend more on the basal ganglia, cerebellum, and amygdala and follow distinct stabilization rules that may not involve the same transcriptional regulators identified in the thalamocortical circuit. The basal ganglia are deep brain structures involved in habit learning and reward-based behaviors.

Explicit and implicit systems interact in everyday experience. A strongly emotional event includes both an explicit representation of what occurred and an implicit emotional response that may guide future anticipation or behavior. Implicit responses are automatic behaviors or feelings triggered without conscious recall. Their interaction helps explain why some events remain behaviorally influential long after their factual details fade.

Established memories can later undergo modification through reconsolidation, a process in which retrieval destabilizes the memory trace, requiring it to be re-stabilized. Memory trace refers to the pattern of neural activity and synaptic changes that encode a memory. Reconsolidation typically requires a prediction error, which occurs when the experience during recall does not match what the memory predicts. Prediction error is the difference between expected and actual outcomes, signaling the need for memory updating. In such cases the memory can be strengthened, weakened, or updated. This adaptive mechanism enables the nervous system to incorporate new information into pre-existing representations rather than preserve outdated ones.

Both consolidation and reconsolidation often require de novo gene expression—the activity-dependent transcription of genes that produce proteins necessary for long-term synaptic and structural change. De novo gene expression does not mean the genes were never active before; rather, their expression increases in response to neural activity. These cascades begin with a calcium influx during neuronal firing, activating kinase pathways such as CaMK and ERK, which in turn phosphorylate transcription factors such as CREB. Calcium influx is the entry of calcium ions into neurons during activation. Kinases are enzymes that add phosphate groups to proteins to modify their activity. Transcription factors like CREB bind DNA and promote gene expression. Chromatin remodeling then increases access to DNA, enabling transcription of genes whose protein products modify synapses. The Rockefeller study extends this model by showing that different phases of long-term memory stabilization rely on different transcriptional regulators acting in sequence and that these regulators operate within specific circuits rather than globally across the brain.

Memory formation is not a simple matter of storing experiences as they occur. Instead, it is a dynamic multi-stage process in which the brain evaluates experiences, stabilizes some, modifies others, and discards most. A multi-stage process means that memory unfolds through several sequential biological phases. The new Rockefeller work illuminates how this evaluation unfolds during the critical post-learning window. A post-learning window is the period immediately after a learning event when the memory remains sensitive to reinforcement or disruption. The research demonstrates that the decision to preserve a memory is guided by the interplay of neuromodulation, prediction error, circuit-specific transcriptional programs, and temporally organized neural activity patterns. Neuromodulation refers to the influence of chemicals that regulate the excitability and plasticity of neurons.

The significance of the new Rockefeller findings lies in their demonstration that long-term memory formation depends on sequential transcriptional programs operating as molecular timers within a defined thalamocortical circuit. This reveals why some memories endure while others fade: each phase of stabilization must be successfully completed at the appropriate time, and different cell types contribute distinct components to the overall process. The study also highlights methodological advances, including single-cell genomic profiling and temporally controlled CRISPR knockouts, that allow causal testing of memory-related gene programs. Single-cell genomic profiling analyzes gene expression at the resolution of individual cells to determine which genes are active in specific cell types. Although these discoveries were made in a specific mouse paradigm and may not generalize automatically to other memory systems or species, they provide a mechanistic framework for understanding why certain experiences become permanently encoded and suggest new directions for studying memory disorders in which these processes fail.

Together, cellular consolidation, systems consolidation, and reconsolidation form an integrated architecture that allows humans to adapt, learn, and continually refine their understanding of the world. An integrated architecture means a group of processes that function in coordination rather than independently. Through this coordinated structure the brain balances stability with flexibility, preserving memories that remain relevant while retaining the capacity to update or discard those that no longer serve.