Dynamical prefrontal population coding during defensive behaviours.

Coping with threatening situations requires both identifying stimuli that predict danger and selecting adaptive behavioural responses to survive1. The dorsomedial prefrontal cortex (dmPFC) is a critical structure that is involved in the regulation of threat-related behaviour2-4. However, it is unclear how threat-predicting stimuli and defensive behaviours are associated within prefrontal networks to successfully drive adaptive responses. Here we used a combination of extracellular recordings, neuronal decoding approaches, pharmacological and optogenetic manipulations to show that, in mice, threat representations and the initiation of avoidance behaviour are dynamically encoded in the overall population activity of dmPFC neurons. Our data indicate that although dmPFC population activity at stimulus onset encodes sustained threat representations driven by the amygdala, it does not predict action outcome. By contrast, transient dmPFC population activity before the initiation of action reliably predicts avoided from non-avoided trials. Accordingly, optogenetic inhibition of prefrontal activity constrained the selection of adaptive defensive responses in a time-dependent manner. These results reveal that the adaptive selection of defensive responses relies on a dynamic process of information linking threats with defensive actions, unfolding within prefrontal networks.

Temporal binding function of dorsal CA1 is critical for declarative memory formation.

Temporal binding, the process that enables association between discontiguous stimuli in memory, and relational organization, a process that enables the flexibility of declarative memories, are both hippocampus-dependent and decline in aging. However, how these two processes are related in supporting declarative memory formation and how they are compromised in age-related memory loss remain hypothetical. We here identify a causal link between these two features of declarative memory: Temporal binding is a necessary condition for the relational organization of discontiguous events. We demonstrate that the formation of a relational memory is limited by the capability of temporal binding, which depends on dorsal (d)CA1 activity over time intervals and diminishes in aging. Conversely, relational representation is successful even in aged individuals when the demand on temporal binding is minimized, showing that relational/declarative memory per se is not impaired in aging. Thus, bridging temporal intervals by dCA1 activity is a critical foundation of relational representation, and a deterioration of this mechanism is responsible for the age-associated memory impairment.

Functional and anatomical relationships between the medial precentral cortex, dorsal striatum, and head direction cell circuitry. I. Recording studies.

Head direction (HD) cells fire as a function of the animal's directional heading and provide the animal with a sense of direction. In rodents, these neurons are located primarily within the limbic system, but small populations of HD cells are found in two extralimbic areas: the medial precentral cortex (PrCM) and dorsal striatum (DS). HD cell activity in these structures could be driven by output from the limbic HD circuit or generated intrinsically. We examined these possibilities by recording the activity of PrCM and DS neurons in control rats and in rats with anterodorsal thalamic nucleus (ADN) lesions, a manipulation that disrupts the limbic HD signal. HD cells in the PrCM and DS of control animals displayed characteristics similar to those of limbic HD cells, and these extralimbic HD signals were eliminated in animals with complete ADN lesions, suggesting that the PrCM and DS HD signals are conveyed from the limbic HD circuit. Angular head velocity cells recorded in the PrCM and DS were unaffected by ADN lesions. Next, we determined if the PrCM and DS convey necessary self-motion signals to the limbic HD circuit. Limbic HD cell activity recorded in the ADN remained intact following combined lesions of the PrCM and DS. Collectively, these experiments reveal a unidirectional functional relationship between the limbic HD circuit and the PrCM and DS; the limbic system generates the HD signal and transmits it to the PrCM and DS, but these extralimbic areas do not provide critical input or feedback to limbic HD cells. NEW & NOTEWORTHY Head direction (HD) cells have been extensively studied within the limbic system. The lesion and recording experiments reported here examined two relatively understudied populations of HD cells located outside of the canonical limbic HD circuit in the medial precentral cortex and dorsal striatum. We found that HD cell activity in these two extralimbic areas is driven by output from the limbic HD circuit, revealing that HD cell circuitry functionally extends beyond the limbic system.

Head Direction Cell Activity Is Absent in Mice without the Horizontal Semicircular Canals.

Head direction (HD) cells fire when an animal faces a particular direction in its environment, and they are thought to represent the neural correlate of the animal's perceived spatial orientation. Previous studies have shown that vestibular information is critical for generating the HD signal but have not delineated whether information from all three semicircular canals or just the horizontal canals, which are primarily sensitive to angular head rotation in the horizontal (yaw) plane, are critical for the signal. Here, we monitored cell activity in the anterodorsal thalamus (ADN), an area known to contain HD cells, in epstatic circler (Ecl) mice, which have a bilateral malformation of the horizontal (lateral) semicircular canals. Ecl mice and their littermates that did not express the mutation (controls) were implanted with recording electrodes in the ADN. Results confirm the important role the horizontal canals play in forming the HD signal. Although normal HD cell activity (Raleigh's r > 0.4) was recorded in control mice, no such activity was found in Ecl mice, although some cells had activity that was mildly modulated by HD (0.4 > r > 0.2). Importantly, we also observed activity in Ecl mice that was best characterized as bursty--a pattern of activity similar to an HD signal but without any preferred firing direction. These results suggest that the neural structure for the HD network remains intact in Ecl mice, but the absence of normal horizontal canals results in an inability to control the network properly and brings about an unstable HD signal. Significance statement: Cells in the anterior dorsal thalamic nucleus normally fire in relation to the animal's directional heading with respect to the environment--so-called head direction cells. To understand how these head direction cells generate their activity, we recorded single-unit activity from the anterior dorsal thalamus in transgenic mice that lack functional horizontal semicircular canals. We show that the neural network for the head direction signal remains intact in these mice, but that the absence of normal horizontal canals results in an inability to control the network properly and brings about an unstable head direction signal.

Is navigation in virtual reality with FMRI really navigation?

Identifying the neural mechanisms underlying spatial orientation and navigation has long posed a challenge for researchers. Multiple approaches incorporating a variety of techniques and animal models have been used to address this issue. More recently, virtual navigation has become a popular tool for understanding navigational processes. Although combining this technique with functional imaging can provide important information on many aspects of spatial navigation, it is important to recognize some of the limitations these techniques have for gaining a complete understanding of the neural mechanisms of navigation. Foremost among these is that, when participants perform a virtual navigation task in a scanner, they are lying motionless in a supine position while viewing a video monitor. Here, we provide evidence that spatial orientation and navigation rely to a large extent on locomotion and its accompanying activation of motor, vestibular, and proprioceptive systems. Researchers should therefore consider the impact on the absence of these motion-based systems when interpreting virtual navigation/functional imaging experiments to achieve a more accurate understanding of the mechanisms underlying navigation.

Switch of serotonergic descending inhibition into facilitation by a spinal chloride imbalance in neuropathic pain.

Descending control from the brain to the spinal cord shapes our pain experience, ranging from powerful analgesia to extreme sensitivity. Increasing evidence from both preclinical and clinical studies points to an imbalance toward descending facilitation as a substrate of pathological pain, but the underlying mechanisms remain unknown. We used an optogenetic approach to manipulate serotonin (5-HT) neurons of the nucleus raphe magnus that project to the dorsal horn of the spinal cord. We found that 5-HT neurons exert an analgesic action in naïve mice that becomes proalgesic in an experimental model of neuropathic pain. We show that spinal KCC2 hypofunction turns this descending inhibitory control into paradoxical facilitation; KCC2 enhancers restored 5-HT-mediated descending inhibition and analgesia. Last, combining selective serotonin reuptake inhibitors (SSRIs) with a KCC2 enhancer yields effective analgesia against nerve injury-induced pain hypersensitivity. This uncovers a previously unidentified therapeutic path for SSRIs against neuropathic pain.

Both visual and idiothetic cues contribute to head direction cell stability during navigation along complex routes.

Successful navigation requires a constantly updated neural representation of directional heading, which is conveyed by head direction (HD) cells. The HD signal is predominantly controlled by visual landmarks, but when familiar landmarks are unavailable, self-motion cues are able to control the HD signal via path integration. Previous studies of the relationship between HD cell activity and path integration have been limited to two or more arenas located in the same room, a drawback for interpretation because the same visual cues may have been perceptible across arenas. To address this issue, we tested the relationship between HD cell activity and path integration by recording HD cells while rats navigated within a 14-unit T-maze and in a multiroom maze that consisted of unique arenas that were located in different rooms but connected by a passageway. In the 14-unit T-maze, the HD signal remained relatively stable between the start and goal boxes, with the preferred firing directions usually shifting <45° during maze traversal. In the multiroom maze in light, the preferred firing directions also remained relatively constant between rooms, but with greater variability than in the 14-unit maze. In darkness, HD cell preferred firing directions showed marginally more variability between rooms than in the lighted condition. Overall, the results indicate that self-motion cues are capable of maintaining the HD cell signal in the absence of familiar visual cues, although there are limits to its accuracy. In addition, visual information, even when unfamiliar, can increase the precision of directional perception.

Directional learning, but no spatial mapping by rats performing a navigational task in an inverted orientation.

Previous studies have identified neurons throughout the rat limbic system that fire as a function of the animal's head direction (HD). This HD signal is particularly robust when rats locomote in the horizontal and vertical planes, but is severely attenuated when locomoting upside-down (Calton & Taube, 2005). Given the hypothesis that the HD signal represents an animal's sense of directional heading, we evaluated whether rats could accurately navigate in an inverted (upside-down) orientation. The task required the animals to find an escape hole while locomoting inverted on a circular platform suspended from the ceiling. In Experiment 1, Long-Evans rats were trained to navigate to the escape hole by locomoting from either one or four start points. Interestingly, no animals from the 4-start point group reached criterion, even after 29 days of training. Animals in the 1-start point group reached criterion after about six training sessions. In Experiment 2, probe tests revealed that animals navigating from either 1- or 2-start points utilized distal visual landmarks for accurate orientation. However, subsequent probe tests revealed that their performance was markedly attenuated when navigating to the escape hole from a novel start point. This absence of flexibility while navigating upside-down was confirmed in Experiment 3 where we show that the rats do not learn to reach a place, but instead learn separate trajectories to the target hole(s). Based on these results we argue that inverted navigation primarily involves a simple directional strategy based on visual landmarks.

Bilateral postsubiculum lesions impair visual and nonvisual homing performance in rats.

Nearly all species rely on visual and nonvisual cues to guide navigation, and which ones they use depend on the environment and task demands. The postsubiculum (PoS) is a crucial brain region for the use of visual cues, but its role in the use of self-movement cues is less clear. We therefore evaluated rats' navigational performance on a food-carrying task in light and in darkness in rats that had bilateral neurotoxic lesions of the PoS. Animals were trained postoperatively to exit a refuge and search for a food pellet, and carry it back to the refuge for consumption. In both light and darkness, control and PoS-lesioned rats made circuitous outward journeys as they searched for food. However, only control rats were able to accurately use visual or self-movement cues to make relatively direct returns to the home refuge. These results suggest the PoS's role in navigation is not limited to the use of visual cues, but also includes the use of self-movement cues. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Protocols to Study Declarative Memory Formation in Mice and Humans:Optogenetics and Translational Behavioral Approaches.

Declarative memory formation depends on the hippocampus and declines in aging. Two functions of the hippocampus, temporal binding and relational organization (Rawlins and Tsaltas, 1983; Eichenbaum et al., 1992 ; Cohen et al., 1997 ), are known to decline in aging (Leal and Yassa, 2015). However, in the literature distinct procedures have been used to study these two functions. Here, we describe the experimental procedures used to investigate how these two processes are related in the formation of declarative memory and how they are compromised in aging ( Sellami et al., 2017 ). First, we studied temporal binding using a one-trial learning procedure: trace fear conditioning. It is classical Pavlovian conditioning requiring temporal binding since a brief temporal gap separates the conditioned stimulus (CS) and unconditioned stimulus (US) presentations. We combined the trace fear condition procedure with an optogenetic approach, and we showed that the temporal binding relies on dorsal (d)CA1 activity over temporal gaps. Then, we studied the interaction between temporal binding and relational organization in declarative memory formation using a two-phase radial-maze task in mice and its virtual analog in humans. The behavioral procedure comprises an initial learning phase where subjects learned the constant rewarding /no rewarding valence of each arm, followed by a test phase where the reward contingencies among the arms remained unchanged but where the arms were recombined to assess flexibility, a cardinal property of declarative memory. We demonstrated that dCA1-dependent temporal binding is necessary for the development of a relational organization of memories that allows flexible declarative memory expression. Furthermore, in aging, the degradation of declarative memory is due to a reduction of temporal binding capacity that prevents relation organization.

Path integration: how the head direction signal maintains and corrects spatial orientation.

Head-direction cells have frequently been regarded as an internal 'compass' that can be used for navigation, although there is little evidence showing a link between their activity and spatial behavior. In a navigational task requiring the use of internal cues to return to a home location without vision (path integration), we found a robust correlation between head-direction cell activity and the rat's heading error in the rat's homing behavior. We observed two different correction processes that rats used to improve performance after an error. The more frequent one consists of 'resetting' the cell whenever the rat returns to the home location. However, we found that when large errors occur, the head-direction system has the ability to 'remap' and set a new reference frame, which is then used in subsequent trials. We also offer some insight into how these two correction processes operate when rats make an error.

The AMPA modulator S 18986 improves declarative and working memory performances in aged mice.

The aim of this study was to further characterize the memory-enhancing profile of S 18986 a positive allosteric modulator of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors. S 18986 was studied in two mouse models of age-related memory deficits, using radial maze paradigms involving long-term/declarative memory and short-term/working memory. Aged mice exhibited severe deficits when compared with their younger counterparts in the two behavioural tests. S 18986 at the dose of 0.1 mg/kg selectively improved aged mouse performance in the test of long-term/declarative memory flexibility and exerted a beneficial effect on short-term retention of successive arm-visits in the short-term/working memory test. This study confirms the memory-enhancing properties of S 18986 and, in line with emerging data on multiple AMPA modulators, highlights the relevance of targeting AMPA receptors in the development of new memory enhancers.