The limbic memory circuit and the neural basis of contextual memory.

The hippocampus, retrosplenial cortex and anterior thalamus are key components of a neural circuit known to be involved in a variety of memory functions, including spatial, contextual and episodic memory. In this review, we focus on the role of this circuit in contextual memory processes. The background environment, or context, is a powerful cue for memory retrieval, and neural representations of the context provide a mechanism for efficiently retrieving relevant memories while avoiding interference from memories that belong to other contexts. Data from experimental lesions and neural manipulation techniques indicate that each of these regions is critical for contextual memory. Neurophysiological evidence from the hippocampus and retrosplenial cortex suggest that contextual information is represented within this circuit by population-level neural firing patterns that reliably differentiate each context a subject encounters. These findings indicate that encoding contextual information to support context-dependent memory retrieval is a key function of this circuit.

Hippocampal state transitions at the boundaries between trial epochs.

The hippocampus encodes distinct contexts with unique patterns of activity. Representational shifts with changes in context, referred to as remapping, have been extensively studied. However, less is known about transitions between representations. In this study, we leverage a large dataset of neuronal recordings taken while rats performed an olfactory memory task with a predictable temporal structure involving trials and intertrial intervals (ITIs), separated by salient boundaries at the trial start and trial end. We found that trial epochs were associated with stable hippocampal representations despite moment-to-moment variability in stimuli and behavior. Representations of trial and ITI epochs were far more distinct than spatial factors would predict and the transitions between the two were abrupt. The boundary was associated with a large spike in multiunit activity, with many individual cells specifically active at the start or end of each trial. Both epochs and boundaries were encoded by hippocampal populations, and these representations carried information on orthogonal axes readily identified using principal component analysis. We suggest that the hippocampus orthogonalizes representations of the trial and ITI epochs and the activity spike at trial boundaries might serve to drive hippocampal activity from one stable state to the other.

Slow stabilization of concurrently acquired hippocampal context representations.

Hippocampal neurons exhibit spatially localized firing patterns that, at the population level, represent a particular environment or context. Many studies have examined how hippocampal neurons switch from an existing representation to a new one when the environment is changed, a process referred to as remapping. New representations were commonly thought to emerge rapidly, within a few minutes and then remain remarkably stable thereafter. However, a number of recent studies suggest that hippocampal representations may be more fluid than previously thought and most of the previous studies only required that subjects switch from a familiar environment to a novel one. In the present study, we examined the concurrent development of two distinct hippocampal representations by exposing rats to two distinct environmental contexts in an ABAB pattern and we recorded neuronal activity for eight daily training sessions. Hippocampal neurons exhibited normal place fields with typical firing properties during the initial exposure to each context on the first day. However, when the rats were returned to the original context after having spent 15 min in the second context, many of the neurons fired in new locations (i.e., they remapped) as if the rat had encountered a new environment. By the third day, the representations had stabilized and were highly consistent across visits to the same context. These results suggest that when subjects concurrently encode multiple contexts, hippocampal representations may require repeated experiences to fully stabilize. © 2016 Wiley Periodicals, Inc.

Placing memories in context: Hippocampal representations promote retrieval of appropriate memories.

Returning to a familiar context triggers retrieval of relevant memories, making memories from other contexts less likely to intrude and cause interference. We investigated the physiology that underlies the use of context to prevent interference by recording hippocampal neurons while rats learned two conflicting sets of discrimination problems, either in the same context or in two distinct contexts. Rats that learned the conflicting problem sets in the same context maintained similar neural representations, and performed poorly because conflicting memories interfered with new learning. In contrast, rats that learned in different contexts formed distinct ensemble representations and performed significantly better. We also measured trial-to-trial variation in representations and found that hippocampal activity was directly linked with performance: on trials where an old representation was active, rats were far more likely to make errors. These results show that the formation of distinct hippocampal representations is critical for contextually appropriate memory retrieval. © 2016 Wiley Periodicals, Inc.

Infralimbic parvalbumin neural activity facilitates cued threat avoidance.

The infralimbic cortex (IL) is essential for flexible behavioral responses to threatening environmental events. Reactive behaviors such as freezing or flight are adaptive in some contexts, but in others a strategic avoidance behavior may be more advantageous. IL has been implicated in avoidance, but the contribution of distinct IL neural subtypes with differing molecular identities and wiring patterns is poorly understood. Here, we study IL parvalbumin (PV) interneurons in mice as they engage in active avoidance behavior, a behavior in which mice must suppress freezing in order to move to safety. We find that activity in inhibitory PV neurons increases during movement to avoid the shock in this behavioral paradigm, and that PV activity during movement emerges after mice have experienced a single shock, prior to learning avoidance. PV neural activity does not change during movement toward cued rewards or during general locomotion in the open field, behavioral paradigms where freezing does not need to be suppressed to enable movement. Optogenetic suppression of PV neurons increases the duration of freezing and delays the onset of avoidance behavior, but does not affect movement toward rewards or general locomotion. These data provide evidence that IL PV neurons support strategic avoidance behavior by suppressing freezing.

Distribution of eye position information in the monkey inferior colliculus.

The inferior colliculus (IC) is thought to have two main subdivisions, a central region that forms an important stop on the ascending auditory pathway and a surrounding shell region that may play a more modulatory role. In this study, we investigated whether eye position affects activity in both the central and shell regions. Accordingly, we mapped the location of eye position-sensitive neurons in six monkeys making spontaneous eye movements by sampling multiunit activity at regularly spaced intervals throughout the IC. We used a functional map based on auditory response patterns to estimate the anatomical location of recordings, in conjunction with structural MRI and histology. We found eye position-sensitive sites throughout the IC, including at 27% of sites in tonotopically organized recording penetrations (putatively the central nucleus). Recordings from surrounding tissue showed a larger proportion of sites indicating an influence of eye position (33-43%). When present, the magnitude of the change in activity due to eye position was often comparable to that seen for sound frequency. Our results indicate that the primary ascending auditory pathway is influenced by the position of the eyes. Because eye position is essential for visual-auditory integration, our findings suggest that computations underlying visual-auditory integration begin early in the ascending auditory pathway.

Tonic activity in lateral habenula neurons acts as a neutral valence brake on reward-seeking behavior.

Survival requires both the ability to persistently pursue goals and the ability to determine when it is time to stop, an adaptive balance of perseverance and disengagement. Neural activity in the lateral habenula (LHb) has been linked to negative valence, but its role in regulating the balance between engaged reward seeking and disengaged behavioral states remains unclear. Here, we show that LHb neural activity is tonically elevated during minutes-long periods of disengagement from reward-seeking behavior, both when due to repeated reward omission (negative valence) and when sufficient reward has been consumed (positive valence). Furthermore, we show that LHb inhibition extends ongoing reward-seeking behavioral states but does not prompt task re-engagement. We find no evidence for similar tonic activity changes in ventral tegmental area dopamine neurons. Our findings support a framework in which tonic activity in LHb neurons suppresses engagement in reward-seeking behavior in response to both negatively and positively valenced factors.

Systematic mapping of the monkey inferior colliculus reveals enhanced low frequency sound representation.

We investigated the functional architecture of the inferior colliculus (IC) in rhesus monkeys. We systematically mapped multiunit responses to tonal stimuli and noise in the IC and surrounding tissue of six rhesus macaques, collecting data at evenly placed locations and recording nonresponsive locations to define boundaries. The results show a modest tonotopically organized region (17 of 100 recording penetration locations in 4 of 6 monkeys) surrounded by a large mass of tissue that, although vigorously responsive, showed no clear topographic arrangement (68 of 100 penetration locations). Rather, most cells in these recordings responded best to frequencies at the low end of the macaque auditory range. The remaining 15 (of 100) locations exhibited auditory responses that were not sensitive to sound frequency. Potential anatomical correlates of functionally defined regions and implications for midbrain auditory prosthetic devices are discussed.

Seeing sounds: visual and auditory interactions in the brain.

Objects and events can often be detected by more than one sensory system. Interactions between sensory systems can offer numerous benefits for the accuracy and completeness of the perception. Recent studies involving visual-auditory interactions have highlighted the perceptual advantages of combining information from these two modalities and have suggested that predominantly unimodal brain regions play a role in multisensory processing.

The form and function of hippocampal context representations.

Context is an essential component of learning and memory processes, and the hippocampus is critical for encoding contextual information. However, connecting hippocampal physiology with its role in context and memory has only recently become possible. It is now clear that contexts are represented by coherent ensembles of hippocampal neurons and new optogenetic stimulation studies indicate that activity in these ensembles can trigger the retrieval of context appropriate memories. We interpret these findings in the light of recent evidence that the hippocampus is critically involved in using contextual information to prevent interference, and propose a theoretical framework for understanding contextual influence on memory retrieval. When a new context is encountered, a unique hippocampal ensemble is recruited to represent it. Memories for events that occur in the context become associated with the hippocampal representation. Revisiting the context causes the hippocampal context code to be re-expressed and the relevant memories are primed. As a result, retrieval of appropriate memories is enhanced and interference from memories belonging to other contexts is minimized.

Distribution of visual and saccade related information in the monkey inferior colliculus.

The inferior colliculus (IC) is an essential stop early in the ascending auditory pathway. Though normally thought of as a predominantly auditory structure, recent work has uncovered a variety of non-auditory influences on firing rate in the IC. Here, we map the location within the IC of neurons that respond to the onset of a fixation-guiding visual stimulus. Visual/visuomotor associated activity was found throughout the IC (overall, 84 of 199 sites tested or 42%), but with a far reduced prevalence and strength along recording penetrations passing through the tonotopically organized region of the IC, putatively the central nucleus (11 of 42 sites tested, or 26%). These results suggest that visual information has only a weak effect on early auditory processing in core regions, but more strongly targets the modulatory shell regions of the IC.