Area-Specificity and Plasticity of History-Dependent Value Coding During Learning.

Decision making is often driven by the subjective value of available options, a value which is formed through experience. To support this fundamental behavior, the brain must encode and maintain the subjective value. To investigate the area specificity and plasticity of value coding, we trained mice in a value-based decision task and imaged neural activity in 6 cortical areas with cellular resolution. History- and value-related signals were widespread across areas, but their strength and temporal patterns differed. In expert mice, the retrosplenial cortex (RSC) uniquely encoded history- and value-related signals with persistent population activity patterns across trials. This unique encoding of RSC emerged during task learning with a strong increase in more distant history signals. Acute inactivation of RSC selectively impaired the reward-history-based behavioral strategy. Our results indicate that RSC flexibly changes its history coding and persistently encodes value-related signals to support adaptive behaviors.

Cerebellar control of a unitary head direction sense.

The head-direction (HD) system, a key neural circuit for navigation, consists of several anatomical structures containing neurons selective to the animal's head direction. HD cells exhibit ubiquitous temporal coordination across brain regions, independently of the animal's behavioral state or sensory inputs. Such temporal coordination mediates a single, stable, and persistent HD signal, which is essential for intact orientation. However, the mechanistic processes behind the temporal organization of HD cells are unknown. By manipulating the cerebellum, we identify pairs of HD cells recorded from two brain structures (anterodorsal thalamus and retrosplenial cortex) that lose their temporal coordination, specifically during the removal of the external sensory inputs. Further, we identify distinct cerebellar mechanisms that participate in the spatial stability of the HD signal depending on sensory signals. We show that while cerebellar protein phosphatase 2B-dependent mechanisms facilitate the anchoring of the HD signal on the external cues, the cerebellar protein kinase C-dependent mechanisms are required for the stability of the HD signal by self-motion cues. These results indicate that the cerebellum contributes to the preservation of a single and stable sense of direction.

Hierarchical Gradients of Encoded Spatial and Sensory Information in the Neocortex Are Attenuated by Dorsal Hippocampal Lesions.

During navigation, the neocortex actively integrates learned spatial context with current sensory experience to guide behaviors. However, the relative encoding of spatial and sensorimotor information among cortical cells, and whether hippocampal feedback continues to modify these properties after learning, remains poorly understood. Thus, two-photon microscopy of male and female Thy1-GCaMP6s mice was used to longitudinally image neurons spanning superficial retrosplenial cortex and layers II-Va of primary and secondary motor cortices before and after bilateral dorsal hippocampal lesions. During behavior on a familiar cued treadmill, the locations of two obstacles were interchanged to decouple place-tuning from cue-tuning among position-correlated cells with fields at those locations. Subpopulations of place and cue cells each formed interareal gradients such that higher-level cortical regions exhibited higher fractions of place cells, whereas lower-level regions exhibited higher fractions of cue cells. Position-correlated cells in the motor cortex also formed translaminar gradients; more superficial cells were more likely to exhibit fields and were more sparsely and precisely tuned than deeper cells. After dorsal hippocampal lesions, a neural representation of the learned environment persisted, but retrosplenial cortex exhibited significantly increased cue-tuning, and, in motor cortices, both position-correlated cell recruitment and population activity at the unstable obstacle locations became more homogeneously elevated across laminae. Altogether, these results support that the hippocampus continues to modulate cortical responses in familiar environments, and the relative impact of descending feedback obeys hierarchical interareal and interlaminar gradients opposite to the flow of ascending sensory inputs.

Hippocampal ripples coincide with "up-state" and spindles in retrosplenial cortex.

During NREM sleep, hippocampal sharp-wave ripple (SWR) events are thought to stabilize memory traces for long-term storage in downstream neocortical structures. Within the neocortex, a set of distributed networks organized around retrosplenial cortex (RS-network) interact preferentially with the hippocampus purportedly to consolidate those traces. Transient bouts of slow oscillations and sleep spindles in this RS-network are often observed around SWRs, suggesting that these two activities are related and that their interplay possibly contributes to memory consolidation. To investigate how SWRs interact with the RS-network and spindles, we combined cortical wide-field voltage imaging, Electrocorticography, and hippocampal LFP recordings in anesthetized and sleeping mice. Here, we show that, during SWR, "up-states" and spindles reliably co-occur in a cortical subnetwork centered around the retrosplenial cortex. Furthermore, retrosplenial transient activations and spindles predict slow gamma oscillations in CA1 during SWRs. Together, our results suggest that retrosplenial-hippocampal interaction may be a critical pathway of information exchange between the cortex and hippocampus.

Learning the Vector Coding of Egocentric Boundary Cells from Visual Data.

The use of spatial maps to navigate through the world requires a complex ongoing transformation of egocentric views of the environment into position within the allocentric map. Recent research has discovered neurons in retrosplenial cortex and other structures that could mediate the transformation from egocentric views to allocentric views. These egocentric boundary cells respond to the egocentric direction and distance of barriers relative to an animal's point of view. This egocentric coding based on the visual features of barriers would seem to require complex dynamics of cortical interactions. However, computational models presented here show that egocentric boundary cells can be generated with a remarkably simple synaptic learning rule that forms a sparse representation of visual input as an animal explores the environment. Simulation of this simple sparse synaptic modification generates a population of egocentric boundary cells with distributions of direction and distance coding that strikingly resemble those observed within the retrosplenial cortex. Furthermore, some egocentric boundary cells learnt by the model can still function in new environments without retraining. This provides a framework for understanding the properties of neuronal populations in the retrosplenial cortex that may be essential for interfacing egocentric sensory information with allocentric spatial maps of the world formed by neurons in downstream areas, including the grid cells in entorhinal cortex and place cells in the hippocampus.SIGNIFICANCE STATEMENT The computational model presented here demonstrates that the recently discovered egocentric boundary cells in retrosplenial cortex can be generated with a remarkably simple synaptic learning rule that forms a sparse representation of visual input as an animal explores the environment. Additionally, our model generates a population of egocentric boundary cells with distributions of direction and distance coding that strikingly resemble those observed within the retrosplenial cortex. This transformation between sensory input and egocentric representation in the navigational system could have implications for the way in which egocentric and allocentric representations interface in other brain areas.

Conjunctive processing of spatial border and locomotion in retrosplenial cortex during spatial navigation.

Spatial information and dynamic locomotor behaviours are equally important for achieving locomotor goals during spatial navigation. However, it remains unclear how spatial and locomotor information is integrated during the processing of self-initiated spatial navigation. Anatomically, the retrosplenial cortex (RSC) has reciprocal connections with brain regions related to spatial processing, including the hippocampus and para-hippocampus, and also receives inputs from the secondary motor cortex. In addition, RSC is functionally associated with allocentric and egocentric spatial targets and head-turning. So, RSC may be a critical region for integrating spatial and locomotor information. In this study, we first examined the role of RSC in spatial navigation using the Morris water maze and found that mice with inactivated RSC took a longer time and distance to reach their destination. Then, by imaging neuronal activity in freely behaving mice within two open fields of different sizes, we identified a large proportion of border cells, head-turning cells and locomotor speed cells in the superficial layer of RSC. Interestingly, some RSC neurons exhibited conjunctive coding for both spatial and locomotor signals. Furthermore, these conjunctive neurons showed higher prediction accuracy compared with simple spatial or locomotor neurons in special navigator scenes using the border, turning and positive-speed conjunctive cells. Our study reveals that the RSC is an important conjunctive brain region that processes spatial and locomotor information during spatial navigation. KEY POINTS: Retrosplenial cortex (RSC) is indispensable during spatial navigation, which was displayed by the longer time and distance of mice to reach their destination after the inactivation of RSC in a water maze. The superficial layer of RSC has a larger population of spatial-related border cells, and locomotion-related head orientation and speed cells; however, it has few place cells in two-dimensional spatial arenas. Some RSC neurons exhibited conjunctive coding for both spatial and locomotor signals, and the conjunctive neurons showed higher prediction accuracy compared with simple spatial or locomotor neurons in special navigation scenes. Our study reveals that the RSC is an important conjunctive brain region that processes both spatial and locomotor information during spatial navigation.

Inhalation of hydrogen gas mitigates sevoflurane-induced neuronal apoptosis in the neonatal cortex and is associated with changes in protein phosphorylation.

Inhalation of hydrogen (H2) gas is therapeutically effective for cerebrovascular diseases, neurodegenerative disorders, and neonatal brain disorders including pathologies induced by anesthetic gases. To understand the mechanisms underlying the protective effects of H2 on the brain, we investigated the molecular signals affected by H2 in sevoflurane-induced neuronal cell death. We confirmed that neural progenitor cells are susceptible to sevoflurane and undergo apoptosis in the retrosplenial cortex of neonatal mice. Co-administration of 1-8% H2 gas for 3 h to sevoflurane-exposed pups suppressed elevated caspase-3-mediated apoptotic cell death and concomitantly decreased c-Jun phosphorylation and activation of the c-Jun pathway, all of which are induced by oxidative stress. Anesthesia-induced increases in lipid peroxidation and oxidative DNA damage were alleviated by H2 inhalation. Phosphoproteome analysis revealed enriched clusters of differentially phosphorylated proteins in the sevoflurane-exposed neonatal brain that included proteins involved in neuronal development and synaptic signaling. H2 inhalation modified cellular transport pathways that depend on hyperphosphorylated proteins including microtubule-associated protein family. These modifications may be involved in the protective mechanisms of H2 against sevoflurane-induced neuronal cell death.

A comparison of hippocampal and retrosplenial cortical spatial and contextual firing patterns.

The hippocampus (HPC) and retrosplenial cortex (RSC) are key components of the brain's memory and navigation systems. Lesions of either region produce profound deficits in spatial cognition and HPC neurons exhibit well-known spatial firing patterns (place fields). Recent studies have also identified an array of navigation-related firing patterns in the RSC. However, there has been little work comparing the response properties and information coding mechanisms of these two brain regions. In the present study, we examined the firing patterns of HPC and RSC neurons in two tasks which are commonly used to study spatial cognition in rodents, open field foraging with an environmental context manipulation and continuous T-maze alternation. We found striking similarities in the kinds of spatial and contextual information encoded by these two brain regions. Neurons in both regions carried information about the rat's current spatial location, trajectories and goal locations, and both regions reliably differentiated the contexts. However, we also found several key differences. For example, information about head direction was a prominent component of RSC representations but was only weakly encoded in the HPC. The two regions also used different coding schemes, even when they encoded the same kind of information. As expected, the HPC employed a sparse coding scheme characterized by compact, high contrast place fields, and information about spatial location was the dominant component of HPC representations. RSC firing patterns were more consistent with a distributed coding scheme. Instead of compact place fields, RSC neurons exhibited broad, but reliable, spatial and directional tuning, and they typically carried information about multiple navigational variables. The observed similarities highlight the closely related functions of the HPC and RSC, whereas the differences in information types and coding schemes suggest that these two regions likely make somewhat different contributions to spatial cognition.

Time cells in the retrosplenial cortex.

The retrosplenial cortex (RSC) is a key component of the brain's memory systems, with anatomical connections to the hippocampus, anterior thalamus, and entorhinal cortex. This circuit has been implicated in episodic memory and many of these structures have been shown to encode temporal information, which is critical for episodic memory. For example, hippocampal time cells reliably fire during specific segments of time during a delay period. Although RSC lesions are known to disrupt temporal memory, time cells have not been observed there. In this study, we reanalyzed archival RSC neuronal firing data during the intertrial delay period from two previous experiments involving different behavioral tasks, a blocked alternation task and a cued T-maze task. For the blocked alternation task, rats were required to approach the east or west arm of a plus maze for reward during different blocks of trials. Because the reward locations were not cued, the rat had to remember the goal location for each trial. In the cued T-maze task, the reward location was explicitly cued with a light and the rats simply had to approach the light for reward, so there was no requirement to hold a memory during the intertrial delay. Time cells were prevalent in the blocked alternation task, and most time cells clearly differentiated the east and west trials. We also found that RSC neurons could exhibit off-response time fields, periods of reliably inhibited firing. Time cells were also observed in the cued T-maze, but they were less prevalent and they did not differentiate left and right trials as well as in the blocked alternation task, suggesting that RSC time cells are sensitive to the memory demands of the task. These results suggest that temporal coding is a prominent feature of RSC firing patterns, consistent with an RSC role in episodic memory.

Psilocybin reduces functional correlation and the encoding of spatial information by neurons in mouse retrosplenial cortex.

Psychedelic drugs have profound effects on perception, cognition and mood. How psychedelics affect neural signaling to produce these effects remains poorly understood. We investigated the effect of the classic psychedelic psilocybin on neural activity patterns and spatial encoding in the retrosplenial cortex of head-fixed mice navigating on a treadmill. The place specificity of neurons to distinct locations along the belt was reduced by psilocybin. Moreover, the stability of place-related activity across trials decreased. Psilocybin also reduced the functional correlation among simultaneously recorded neurons. The 5-HT2AR (serotonin 2A receptor) antagonist ketanserin blocked these effects. These data are consistent with proposals that psychedelics increase the entropy of neural signaling and provide a potential neural mechanism contributing to disorientation frequently reported by humans after taking psychedelics.

Disrupting direct inputs from the dorsal subiculum to the granular retrosplenial cortex impairs flexible spatial memory in the rat.

In a changing environment, animals must process spatial signals in a flexible manner. The rat hippocampal formation projects directly upon the retrosplenial cortex, with most inputs arising from the dorsal subiculum and terminating in the granular retrosplenial cortex (area 29). The present study examined whether these same projections are required for spatial working memory and what happens when available spatial cues are altered. Consequently, injections of iDREADDs were made into the dorsal subiculum of rats. In a separate control group, GFP-expressing adeno-associated virus was injected into the dorsal subiculum. Both groups received intracerebral infusions within the retrosplenial cortex of clozapine, which in the iDREADDs rats should selectively disrupt the subiculum to retrosplenial projections. When tested on reinforced T-maze alternation, disruption of the subiculum to retrosplenial projections had no evident effect on the performance of those alternation trials when all spatial-cue types remained present and unchanged. However, the same iDREADDs manipulation impaired performance on all three alternation conditions when there was a conflict or selective removal of spatial cues. These findings reveal how the direct projections from the dorsal subiculum to the retrosplenial cortex support the flexible integration of different spatial cue types, helping the animal to adopt the spatial strategy that best meets current environmental demands.

Neuronal network controlling REM sleep.

Rapid eye movement sleep is a state characterized by concomitant occurrence of rapid eye movements, electroencephalographic activation and muscle atonia. In this review, we provide up to date knowledge on the neuronal network controlling its onset and maintenance. It is now accepted that muscle atonia during rapid eye movement sleep is due to activation of glutamatergic neurons localized in the pontine sublaterodorsal tegmental nucleus. These neurons directly project and excite glycinergic/γ-aminobutyric acid-ergic pre-motoneurons localized in the ventromedial medulla. The sublaterodorsal tegmental nucleus rapid eye movement-on neurons are inactivated during wakefulness and non-rapid eye movement by rapid eye movement-off γ-aminobutyric acid-ergic neurons localized in the ventrolateral periaqueductal grey and the adjacent dorsal deep mesencephalic reticular nucleus. Melanin-concentrating hormone and γ-aminobutyric acid-ergic rapid eye movement sleep-on neurons localized in the lateral hypothalamus would inhibit these rapid eye movement sleep-off neurons initiating the state. Finally, the activation of a few limbic cortical structures during rapid eye movement sleep by the claustrum and the supramammillary nucleus as well as that of the basolateral amygdala would be involved in the function(s) of rapid eye movement sleep. In summary, rapid eye movement sleep is generated by a brainstem generator controlled by forebrain structures involved in autonomic control.

Astrocytic P2X7 receptor in retrosplenial cortex drives electroacupuncture analgesia.

P2X7 receptor (P2X7R) has been found to contribute to the peripheral mechanism of acupuncture analgesia (AA). However, whether it plays an important role in central mechanism remains unknown. In this study, we aimed to reveal the role of astrocytic P2X7R in retrosplenial cortex (RSC) in AA and provide new evidence for underlying the central mechanism of AA. We applied the chemogenetic receptors hM3Dq to stimulate or hM4Di to inhibit astrocytes ligand clozapine-N-oxide (CNO) following injection of adeno-associated virus (AAV) into the bilateral RSC, or pharmacologically intervened in the activity of the purinergic receptor P2X7R. Current data indicated that chemogenetic inhibition of astrocytes or injection of P2X7R agonist Bz-ATP in the bilateral RSC significantly reverses the analgesic effect of electroacupuncture (EA) in formalin tests while the bilateral injection of the P2X7R antagonist A438079 alleviated formalin-induced nociceptive behavior. Additionally, chemogenetic suppression of astrocytic P2X7R by injection of AAV in the bilateral RSC decreased hind paw flinches induced by formalin in the mice. These findings indicate the participation of both astrocytes and P2X7R in the RSC in EA analgesic. Moreover, P2X7R on astrocytes in the RSC appears to play a critical role in the ability of EA to attenuate formalin-induced pain responses in mice.

Distinct Contribution of Granular and Agranular Subdivisions of the Retrosplenial Cortex to Remote Contextual Fear Memory Retrieval.

The retrieval of recent and remote memories are thought to rely on distinct brain circuits and mechanisms. The retrosplenial cortex (RSC) is robustly activated during the retrieval of remotely acquired contextual fear memories (CFMs), but the contribution of particular subdivisions [granular (RSG) vs agranular retrosplenial area (RSA)] and the circuit mechanisms through which they interact to retrieve remote memories remain unexplored. In this study, using both anterograde and retrograde viral tracing approaches, we identified excitatory projections from layer 5 pyramidal neurons of the RSG to the CA1 stratum radiatum/lacunosum-moleculare of the dorsal hippocampus and the superficial layers of the RSA in male mice. We found that chemogenetic or optogenetic inhibition of the RSG-to-CA1, but not the RSG-to-RSA, pathway selectively impairs the retrieval of remote CFMs. Collectively, our results uncover a specific role for the RSG in remote CFM recall and provide circuit evidence that RSG-mediated remote CFM retrieval relies on direct RSG-to-CA1 connectivity. The present study provides a better understanding of brain circuit mechanisms underlying the retrieval of remote CFMs and may help guide the development of therapeutic strategies to attenuate remote traumatic memories that lead to mental health issues such as post-traumatic stress disorder.SIGNIFICANCE STATEMENT The RSC is implicated in contextual information processing and remote recall. However, how different subdivisions of the RSC and circuit mechanisms through which they interact to underlie remote memory recall remain unexplored. This study shows that granular subdivision of the RSC and its input to hippocampal area CA1 contributes to the retrieval of remote contextual fear memories. Our results support the hypothesis that the RSC and hippocampus require each other to preserve fear memories and may provide a novel therapeutic avenue to attenuate remote traumatic memories in patients with post-traumatic stress disorder.

Environment Symmetry Drives a Multidirectional Code in Rat Retrosplenial Cortex.

We investigated how environment symmetry shapes the neural processing of direction by recording directionally tuned retrosplenial neurons in male Lister hooded rats exploring multicompartment environments that had different levels of global rotational symmetry. Our hypothesis built on prior observations of twofold symmetry in the directional tuning curves of rats in a globally twofold-symmetric environment. To test whether environment symmetry was the relevant factor shaping the directional responses, here we deployed the same apparatus (two connected rectangular boxes) plus one with fourfold symmetry (a 2 × 2 array of connected square boxes) and one with onefold symmetry (a circular open-field arena). Consistent with our hypothesis we found many neurons with tuning curve symmetries that mirrored these environment symmetries, having twofold, fourfold, or onefold symmetric tuning, respectively. Some cells expressed this pattern only globally (across the whole environment), maintaining singular tuning curves in each subcompartment. However, others also expressed it locally within each subcompartment. Because multidirectionality has not been reported in naive rats in single environmental compartments, this suggests an experience-dependent effect of global environment symmetry on local firing symmetry. An intermingled population of directional neurons were classic head direction cells with globally referenced directional tuning. These cells were electrophysiologically distinct, with narrower tuning curves and a burstier firing pattern. Thus, retrosplenial directional neurons can simultaneously encode overall head direction and local head direction (relative to compartment layout). Furthermore, they can learn about global environment symmetry and express this locally. This may be important for the encoding of environment structure beyond immediate perceptual reach.SIGNIFICANCE STATEMENT We investigated how environment symmetry shapes the neural code for space by recording directionally tuned neurons from the retrosplenial cortex of rats exploring single- or multicompartment environments having onefold, twofold, or fourfold rotational symmetry. We found that many cells expressed a symmetry in their head direction tuning curves that matched the corresponding global environment symmetry, indicating plasticity of their directional tuning. They were also electrophysiologically distinct from canonical head directional cells. Notably, following exploration of the global space, many multidirectionally tuned neurons encoded global environment symmetry, even in local subcompartments. Our results suggest that multidirectional head direction codes contribute to the cognitive mapping of the complex structure of multicompartmented spaces.

ß Bursting in the Retrosplenial Cortex Is a Neurophysiological Correlate of Environmental Novelty Which Is Disrupted in a Mouse Model of Alzheimer's Disease.

The retrosplenial cortex (RSC) plays a significant role in spatial learning and memory and is functionally disrupted in the early stages of Alzheimer's disease (AD). In order to investigate neurophysiological correlates of spatial learning and memory in this region we employed in vivo electrophysiology in awake and freely moving male mice, comparing neural activity between wild-type and J20 mice, a transgenic model of AD-associated amyloidopathy. To determine the response of the RSC to environmental novelty local field potentials (LFPs) were recorded while mice explored novel and familiar recording arenas. In familiar environments we detected short, phasic bursts of ß (20-30 Hz) oscillations (ß bursts), which arose at a low but steady rate. Exposure to a novel environment rapidly initiated a dramatic increase in the rate, size and duration of ß bursts. Additionally, θ-α/ß cross-frequency coupling was significantly higher during novelty, and spiking of neurons in the RSC was significantly enhanced during ß bursts. Finally, excessive ß bursting was seen in J20 mice, including increased ß bursting during novelty and familiarity, yet a loss of coupling between ß bursts and spiking activity. These findings support the concept that ß bursting may be responsible for the activation and reactivation of neuronal ensembles underpinning the formation and maintenance of cortical representations, and that disruptions to this activity in J20 mice may underlie cognitive impairments seen in these animals.SIGNIFICANCE STATEMENT The retrosplenial cortex (RSC) is thought to be involved in the formation, recall and consolidation of contextual memory. The discovery of bursts of ß oscillations in this region, which are associated with increased neuronal spiking and strongly upregulated while mice explore novel environments, provides a potential mechanism for the activation of neuronal ensembles, which may underlie the formation of cortical representations of context. Excessive ß bursting in the RSC of J20 mice, a mouse model of Alzheimer's disease (AD), alongside the disassociation of ß bursting from neuronal spiking, may underlie spatial memory impairments previously shown in these mice. These findings introduce a novel neurophysiological correlate of spatial learning and memory, and a potentially new form of AD-related cortical dysfunction.

The human posterior cingulate, retrosplenial, and medial parietal cortex effective connectome, and implications for memory and navigation.

The human posterior cingulate, retrosplenial, and medial parietal cortex are involved in memory and navigation. The functional anatomy underlying these cognitive functions was investigated by measuring the effective connectivity of these Posterior Cingulate Division (PCD) regions in the Human Connectome Project-MMP1 atlas in 171 HCP participants, and complemented with functional connectivity and diffusion tractography. First, the postero-ventral parts of the PCD (31pd, 31pv, 7m, d23ab, and v23ab) have effective connectivity with the temporal pole, inferior temporal visual cortex, cortex in the superior temporal sulcus implicated in auditory and semantic processing, with the reward-related vmPFC and pregenual anterior cingulate cortex, with the inferior parietal cortex, and with the hippocampal system. This connectivity implicates it in hippocampal episodic memory, providing routes for "what," reward and semantic schema-related information to access the hippocampus. Second, the antero-dorsal parts of the PCD (especially 31a and 23d, PCV, and also RSC) have connectivity with early visual cortical areas including those that represent spatial scenes, with the superior parietal cortex, with the pregenual anterior cingulate cortex, and with the hippocampal system. This connectivity implicates it in the "where" component for hippocampal episodic memory and for spatial navigation. The dorsal-transitional-visual (DVT) and ProStriate regions where the retrosplenial scene area is located have connectivity from early visual cortical areas to the parahippocampal scene area, providing a ventromedial route for spatial scene information to reach the hippocampus. These connectivities provide important routes for "what," reward, and "where" scene-related information for human hippocampal episodic memory and navigation. The midcingulate cortex provides a route from the anterior dorsal parts of the PCD and the supracallosal part of the anterior cingulate cortex to premotor regions.

From safety to frustration: The neural substrates of inhibitory learning in aversive and appetitive conditioning procedures.

Inhibitory associative learning counters the effects of excitatory learning, whether appetitively or aversively motivated. Moreover, the affective responses accompanying the inhibitory associations are of opponent valence to the excitatory conditioned responses. Inhibitors for negative aversive outcomes (e.g. shock) signal safety, while inhibitors for appetitive outcomes (e.g. food reward) elicit frustration and/or disappointment. This raises the question as to whether studies using appetitive and aversive conditioning procedures should demonstrate the same neural substrates for inhibitory learning. We review the neural substrates of appetitive and aversive inhibitory learning as measured in different procedural variants and in the context of the underpinning excitatory conditioning on which it depends. The mesocorticolimbic dopamine pathways, retrosplenial cortex and hippocampus are consistently implicated in inhibitory learning. Further neural substrates identified in some procedural variants may be related to the specific motivation of the learning task and modalities of the learning cues. Finally, we consider the translational implications of our understanding of the neural substrates of inhibitory learning, for obesity and addictions as well as for anxiety disorders.

Unique roles for the anterior and posterior retrosplenial cortices in encoding and retrieval of memory for context.

The rat retrosplenial cortex (RSC) makes critical contributions to learning and memory but these contributions may not be uniform along its rostro-caudal axis. Previous work suggests that event-related and context-related information are differentially encoded by anterior and posterior RSC subregions. Here, we further test this idea using a procedure in which spatial/environmental cues (context) and discrete event memories are acquired separately. All animals received a 5-min pre-exposure to the training context 24 h before contextual fear conditioning where shock was delivered immediately upon being placed in the chamber. Rats were tested for memory for the context the next day. We found that optogenetic inhibition of cells in only the posterior RSC during the pre-exposure phase, when spatial information is encoded, reduced behavioral responding during the subsequent memory test. However, similar inhibition of either the anterior or posterior RSC during shock delivery, when information about both the context and the shock become integrated, impaired memory. Finally, inhibiting cellular activity in only the posterior RSC during memory retrieval during testing reduced responding. Together, these results suggest that while activity in both subregions is needed during the period in which the event-related information becomes integrated with the context representation, the posterior RSC is important for both memory formation and retrieval or expression of memory for information about the context. These results add to a growing literature demonstrating a role for the RSC in integration of multiple aspects of memory, and provide information on how spatial representations reliant on the retrosplenial cortex interact with associative learning.

Wide-Field Calcium Imaging of Dynamic Cortical Networks during Locomotion.

Motor behavior results in complex exchanges of motor and sensory information across cortical regions. Therefore, fully understanding the cerebral cortex's role in motor behavior requires a mesoscopic-level description of the cortical regions engaged, their functional interactions, and how these functional interactions change with behavioral state. Mesoscopic Ca2+ imaging through transparent polymer skulls in mice reveals elevated activation of the dorsal cerebral cortex during locomotion. Using the correlations between the time series of Ca2+ fluorescence from 28 regions (nodes) obtained using spatial independent component analysis (sICA), we examined the changes in functional connectivity of the cortex from rest to locomotion with a goal of understanding the changes to the cortical functional state that facilitate locomotion. Both the transitions from rest to locomotion and from locomotion to rest show marked increases in correlation among most nodes. However, once a steady state of continued locomotion is reached, many nodes, including primary motor and somatosensory nodes, show decreases in correlations, while retrosplenial and the most anterior nodes of the secondary motor cortex show increases. These results highlight the changes in functional connectivity in the cerebral cortex, representing a series of changes in the cortical state from rest to locomotion and on return to rest.