Electrophysiological Signatures of Visual Recognition Memory across All Layers of Mouse V1.

In mouse primary visual cortex (V1), familiar stimuli evoke significantly altered responses when compared with novel stimuli. This stimulus-selective response plasticity (SRP) was described originally as an increase in the magnitude of visual evoked potentials (VEPs) elicited in layer 4 (L4) by familiar phase-reversing grating stimuli. SRP is dependent on NMDA receptors (NMDARs) and has been hypothesized to reflect potentiation of thalamocortical (TC) synapses in L4. However, recent evidence indicates that the synaptic modifications that manifest as SRP do not occur on L4 principal cells. To shed light on where and how SRP is induced and expressed in male and female mice, the present study had three related aims: (1) to confirm that NMDAR are required specifically in glutamatergic principal neurons of V1, (2) to investigate the consequences of deleting NMDAR specifically in L6, and (3) to use translaminar electrophysiological recordings to characterize SRP expression in different layers of V1. We find that knock-out (KO) of NMDAR in L6 principal neurons disrupts SRP. Current-source density (CSD) analysis of the VEP depth profile shows augmentation of short latency current sinks in layers 3, 4, and 6 in response to phase reversals of familiar stimuli. Multiunit recordings demonstrate that increased peak firing occurs in response to phase reversals of familiar stimuli across all layers, but that activity between phase reversals is suppressed. Together, these data reveal important aspects of the underlying phenomenology of SRP and generate new hypotheses for the expression of experience-dependent plasticity in V1.SIGNIFICANCE STATEMENT Repeated exposure to stimuli that portend neither reward nor punishment leads to behavioral habituation, enabling organisms to dedicate attention to novel or otherwise significant features of the environment. The neural basis of this process, which is so often dysregulated in neurologic and psychiatric disorders, remains poorly understood. Learning and memory of stimulus familiarity can be studied in mouse visual cortex by measuring electrophysiological responses to simple phase-reversing grating stimuli. The current study advances knowledge of this process by documenting changes in visual evoked potentials (VEPs), neuronal spiking activity, and oscillations in the local field potentials (LFPs) across all layers of mouse visual cortex. In addition, we identify a key contribution of a specific population of neurons in layer 6 (L6) of visual cortex.

Electrophysiological signatures of visual recognition memory across all layers of mouse V1.

In mouse primary visual cortex (V1), familiar stimuli evoke significantly altered responses when compared to novel stimuli. This stimulus-selective response plasticity (SRP) was described originally as an increase in the magnitude of visual evoked potentials (VEPs) elicited in layer (L) 4 by familiar phase-reversing grating stimuli. SRP is dependent on NMDA receptors (NMDAR) and has been hypothesized to reflect potentiation of thalamocortical synapses in L4. However, recent evidence indicates that the synaptic modifications that manifest as SRP do not occur on L4 principal cells. To shed light on where and how SRP is induced and expressed, the present study had three related aims: (1) to confirm that NMDAR are required specifically in glutamatergic principal neurons of V1, (2) to investigate the consequences of deleting NMDAR specifically in L6, and (3) to use translaminar electrophysiological recordings to characterize SRP expression in different layers of V1. We find that knockout of NMDAR in L6 principal neurons disrupts SRP. Current-source density analysis of the VEP depth profile shows augmentation of short latency current sinks in layers 3, 4 and 6 in response to phase reversals of familiar stimuli. Multiunit recordings demonstrate that increased peak firing occurs to in response to phase reversals of familiar stimuli across all layers, but that activity between phase reversals is suppressed. Together, these data reveal important aspects of the underlying phenomenology of SRP and generate new hypotheses for the expression of experience-dependent plasticity in V1. Significance Statement: Repeated exposure to stimuli that portend neither reward nor punishment leads to behavioral habituation, enabling organisms to dedicate attention to novel or otherwise significant features of the environment. The neural basis of this process, which is so often dysregulated in neurological and psychiatric disorders, remains poorly understood. Learning and memory of stimulus familiarity can be studied in mouse visual cortex by measuring electrophysiological responses to simple phase-reversing grating stimuli. The current study advances knowledge of this process by documenting changes in visual evoked potentials, neuronal spiking activity, and oscillations in the local field potentials across all layers of mouse visual cortex. In addition, we identify a key contribution of a specific population of neurons in layer 6 of visual cortex.

The spatiotemporal organization of experience dictates hippocampal involvement in primary visual cortical plasticity.

The hippocampus and neocortex are theorized to be crucial partners in the formation of long-term memories. Here, we assess hippocampal involvement in two related forms of experience-dependent plasticity in the primary visual cortex (V1) of mice. Like control animals, those with hippocampal lesions exhibit potentiation of visually evoked potentials after passive daily exposure to a phase-reversing oriented grating stimulus, which is accompanied by long-term habituation of a reflexive behavioral response. Thus, low-level recognition memory is formed independently of the hippocampus. However, response potentiation resulting from daily exposure to a fixed sequence of four oriented gratings is severely impaired in mice with hippocampal damage. A feature of sequence plasticity in V1 of controls, which is absent in lesioned mice, is the generation of predictive responses to an anticipated stimulus element when it is withheld or delayed. Thus, the hippocampus is involved in encoding temporally structured experience, even within the primary sensory cortex.

Amyloid Beta Secreted during Consolidation Prevents Memory Malleability.

Memory allows organisms to predict future events based on their prior sampling of the world. Rather than faithfully encoding each detail of related episodes, the brain is thought to incrementally construct probabilistic estimates of environmental statistics that are re-evaluated each time relevant events are encountered [1]. When faced with evidence that does not adequately fit mnemonic predictions, a process called reconsolidation can alter relevant memories to better recapitulate ongoing experience [2]. Conversely, when an ongoing event matches well-established predictions, reactivated memories tend to remain stable [3, 4]. In part, the brain may confer selective mnemonic stability by shifting cell-intrinsic mechanisms of plasticity induction [5], which could serve to constrain maladaptive updating of reliably predictive representations during anomalous events. Based on evidence of decreased cognitive flexibility and restricted synaptic plasticity in later life [6], we hypothesized that some prevalent age-associated neurobiological changes might in fact contribute to mnemonic stability [7]. Specifically, we predicted that amyloid beta (Aß)-a peptide that often accumulates in the brains of individuals expressing senescent dementia [8-10]-is required for memory stabilization. Indeed, we observe elevated soluble Aßx-42 concentrations in the amygdala shortly after young adult rats form reconsolidation-resistant auditory fear memories. Suppressing secretases required for Aß production immediately after learning prevents mnemonic stabilization, rendering these memories vulnerable to disruption by post-reactivation amnestic treatments. Thus, the seemingly pathogenic Aß42 peptide may serve an adaptive physiological function during memory consolidation by engaging mechanisms that protect reliably predictive representations against subsequent modification.

Cortico-hippocampal Schemas Enable NMDAR-Independent Fear Conditioning in Rats.

The neurobiology of memory formation has been studied primarily in experimentally naive animals, but the majority of learning unfolds on a background of prior experience. Considerable evidence now indicates that the brain processes initial and subsequent learning differently. In rodents, a first instance of contextual fear conditioning requires NMDA receptor (NMDAR) activation in the dorsal hippocampus, but subsequent conditioning to another context does not. This shift may result from a change in molecular plasticity mechanisms or in the information required to learn the second task. To clarify how related events are encoded, it is critical to identify which aspect of a first task engages NMDAR-independent learning and the brain regions that maintain this state. Here, we show in rats that the requirement for NMDARs in hippocampus depends neither on prior exposure to context nor footshock alone but rather on the procedural similarity between two conditioning tasks. Importantly, NMDAR-independent learning requires the memory of the first task to remain hippocampus dependent. Furthermore, disrupting memory maintenance in the anterior cingulate cortex after the first task also reinstates NMDAR dependency. These results reveal cortico-hippocampal interactions supporting experience-dependent learning.

Limits on lability: Boundaries of reconsolidation and the relationship to metaplasticity.

Reconsolidation, a process by which long-term memories are rendered malleable following retrieval, has been shown to occur across many different species and types of memory. However, there are conditions under which memories do not reconsolidate, and the reasons for this are poorly understood. One emerging theory is that these boundary conditions are mediated by a form of metaplasticity: cellular changes through which experience can affect future synaptic plasticity. We review evidence that N-methyl-D-aspartate receptors (NMDARs) might contribute to this phenomenon, and hypothesize that resistance to memory destabilization may be mediated by the ratio of GluN2A/GluN2B subunits that make up these receptors. Qualities such as memory strength and the age of the memory may increase the GluN2A/GluN2B ratio, reducing the ability of reactivation cues to induce destabilization, thereby preventing reconsolidation. Other examples of experience-dependent learning and evolutionary perspectives of reconsolidation are also discussed.

Dorsal hippocampus is necessary for novel learning but sufficient for subsequent similar learning.

Our current understanding of brain mechanisms involved in learning and memory has been derived largely from studies using experimentally naïve animals. However, it is becoming increasingly clear that not all identified mechanisms may generalize to subsequent learning. For example, N-methyl-D-aspartate glutamate (NMDA) receptors in the dorsal hippocampus are required for contextual fear conditioning in naïve animals but not in animals previously trained in a similar task. Here we investigated how animals learn contextual fear conditioning for a second time-a response which is not due to habituation or generalization. We found that dorsal hippocampus infusions of voltage-dependent calcium channel blockers or the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) agonist impaired the first, not the second contextual learning. Only manipulations of the entire hippocampus led to an impairment in second learning. Specifically, inactivation of either the dorsal or ventral hippocampus caused the remaining portion of the hippocampus to acquire and consolidate the second learning. Thus, dorsal hippocampus seems necessary for initial contextual fear conditioning, but either the dorsal or ventral hippocampus is sufficient for subsequent conditioning in a different context. Together, these findings suggest that prior training experiences can change how the hippocampus processes subsequent similar learning.

The role of metaplasticity mechanisms in regulating memory destabilization and reconsolidation.

Memory allows organisms to predict future events based on prior experiences. This requires encoded information to persist once important predictors are extracted, while also being modifiable in response to changes within the environment. Memory reconsolidation may allow stored information to be modified in response to related experience. However, there are many boundary conditions beyond which reconsolidation may not occur. One interpretation of these findings is that the event triggering memory retrieval must contain new information about a familiar stimulus in order to induce reconsolidation. Presently, the mechanisms that affect the likelihood of reconsolidation occurring under these conditions are not well understood. Here we speculate on a number of systems that may play a role in protecting memory from being destabilized during retrieval. We conclude that few memories may enter a state in which they cannot be modified. Rather, metaplasticity mechanisms may serve to alter the specific reactivation cues necessary to destabilize a memory. This might imply that destabilization mechanisms can differ depending on learning conditions.