Active forgetting and neuropsychiatric diseases

Abstract

Recent and pioneering animal research has revealed the brain utilizes a variety of molecular, cellular, and network-level mechanisms used to forget memories in a process referred to as "active forgetting". Active forgetting increases behavioral flexibility and removes irrelevant information. Individuals with impaired active forgetting mechanisms can experience intrusive memories, distressing thoughts, and unwanted impulses that occur in neuropsychiatric diseases. The current evidence indicates that active forgetting mechanisms degrade, or mask, molecular and cellular memory traces created in synaptic connections of "engram cells" that are specific for a given memory. Combined molecular genetic/behavioral studies using Drosophila have uncovered a complex system of cellular active-forgetting pathways within engram cells that is regulated by dopamine neurons and involves dopamine-nitric oxide co-transmission and reception, endoplasmic reticulum Ca²⁺ signaling, and cytoskeletal remodeling machinery regulated by small GTPases. Some of these molecular cellular mechanisms have already been found to be conserved in mammals. Interestingly, some pathways independently regulate forgetting of distinct memory types and temporal phases, suggesting a multi-layering organization of forgetting systems. In mammals, active forgetting also involves modulation of memory trace synaptic strength by altering AMPA receptor trafficking. Furthermore, active-forgetting employs network level mechanisms wherein non-engram neurons, newly born-engram neurons, and glial cells regulate engram synapses in a state and experience dependent manner. Remarkably, there is evidence for potential coordination between the network and cellular level forgetting mechanisms. Finally, subjects with several neuropsychiatric diseases have been tested and shown to be impaired in active forgetting. Insights obtained from research on active forgetting in animal models will continue to enrich our understanding of the brain dysfunctions that occur in neuropsychiatric diseases.

Fig. 1. Principal memory operations and cellular events.

a The nervous system uses four operations for short- and long-term memory formation: Acquisition, Consolidation, Forgetting, and Retrieval. Acquisition is synonymous with “learning,” and represents the initial encoding of information. Consolidation refers to the processes involved in stabilizing memory over time. Forgetting involves mechanisms whereby memories can be erased or hidden from retrieval. Retrieval is simply the recollection, or recall, of existing memories. b Cartoon illustrating the broad cellular and network events of memory formation. During acquisition, selected cells in the nervous system undergo molecular or biochemical changes that alter their physiological state. These selected cells are known as engram cells, and the molecular or biochemical changes within the engram cells are termed molecular or cellular memory traces. Consolidation mechanisms stabilize the cellular memory traces and the selected engram cells. The engram cells and their corresponding memory traces, together, represent the overall “engram” for a given memory. The activity of forgetting cells can erode the memory traces and cause memory failure.

Fig. 2. Dopamine neuron mediated active forgetting pathways in Drosophila.

Dopamine neurons (DAn) modulate forgetting by driving independent active forgetting pathways within engram synapses (MBn:MBOn) using co-transmitters NO and DA. DA signaling through the MBn expressed DAMB receptor drives forgetting through two fundamental pathways: 1) coupling to Gαq to drive ER Ca2+ release in MBn synapses, or 2) signaling through Scribble/Rac1 complex to regulate actin remodeling. In parallel, DAn terminals synthesize NO gas that diffuses into MBn and binds the Guanylyl Cyclase (GC, or GycB100) and generates cGMP. NO mediated effects require Scribble. DAn->NO->cGMP signaling also drives gene-expression based forgetting through co-localization of Kdm4B/Bur to genomic sites. Kdm4B/Bur activity drives expression of many genes and enlargement of MBn synapses, possibly through Kek2 expression.

Fig. 3. Distinct signaling regulates forgetting of different memory phases and types in Drosophila.

A single trial of aversive olfactory conditioning yields a short-lived memory that is labile and anesthesia-sensitive (ASM) and a consolidated form of memory that is longer-lasting and anesthesia-resistant (ARM). Retention of STM (black line) and its ASM (red) and ARM (blue) components over time require distinct and sequentially engaged cellular pathways. Upon learning, labile ASM is formed and within 1 hour a consolidated ARM component forms. The forgetting of ASM proceeds rapidly through the activation of the Rac1 within the first 3 hours. Raf is also activated during this period and blocks forgetting of a Rac1 independent form of ASM. Gene expression-based forgetting from Kdm4B/Bur activity regulates forgetting of ASM between 3–6 hours. The forgetting of consolidated ARM proceeds through the activation of Cdc42 between 3–6 hours after learning. After 6 hr memory slowly decays, but the forgetting pathways responsible are unknown (??).

Fig. 4. Multiple actin remodeling pathways differentially regulate forgetting of specific memory types in Drosophila.

Actin cytoskeletal remodeling regulates the forgetting of both labile (ASM) and consolidated (ARM) memories in Drosophila through independent actin regulators and pathways. Small GTPase Rac1 regulates forgetting of ASM through two distinct pathways. Downstream of DA signaling, Rac1 associates with Scribble and Pak3 to inhibit Cofilin and stop actin depolymerization. In parallel, Rac1 drives linear actin polymerization via SCAR mediated Dia activity. A portion of ASM is protected from disruption by Raf phosphorylation of MAPK and subsequent activation of the Myosin II motor. This could lead to translocation of actin filaments and tension that potentially supports enlarged synaptic size required to store memory. Another small GTPase Cdc42 regulates ARM by WASp mediated activation of the Arp2/3 complex to increase polymerization of branched actin.

Fig. 5. Active forgetting pathways in mammals involve AMPAR trafficking.

Multiple forgetting pathways in mammals utilize glutamatergic receptor AMPAR endocytosis to modulate the strength of engram synapses. One such pathway involves the activation of Caspase-2, which subsequently increases GSK3β kinase activity. In turn, GSK3β phosphorylates AMPARs, initiating their internalization. A second and independent forgetting pathway involves Syt3 integral membrane protein and Ca²⁺ dependent internalization of AMPARs.

Fig. 6. Network level regulation of forgetting.

Forgetting involves multiple network level mechanisms that regulate engram cell (EC) synapses. An existing memory engram is stored across engram cells and their synaptic connections (blue). These EC are modulated by external circuits (red) that respond to sensory experience or internal states and regulate EC synaptic strength and thus regulate forgetting. Additionally, neurogenesis drives the creation of new engram cells (purple) that compete for synaptic inputs and outputs with existing engram cells storing pre-existing memories. Here, “+” indicates the recent addition of a synapse between new EC and existing EC. Finally, weaker engram synapses are targeted for phagocytosis and elimination by microglia (green).