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.

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.

Dual-Factor Representation of the Environmental Context in the Retrosplenial Cortex.

The retrosplenial cortex (RSC) is thought to be involved in a variety of spatial and contextual memory processes. However, we do not know how contextual information might be encoded in the RSC or whether the RSC representations may be distinct from context representations seen in other brain regions such as the hippocampus. We recorded RSC neuronal responses while rats explored different environments and discovered 2 kinds of context representations: one involving a novel rate code in which neurons reliably fire at a higher rate in the preferred context regardless of spatial location, and a second involving context-dependent spatial firing patterns similar to those seen in the hippocampus. This suggests that the RSC employs a unique dual-factor representational mechanism to support contextual memory.

Retrosplenial Cortical Neurons Encode Navigational Cues, Trajectories and Reward Locations During Goal Directed Navigation.

The retrosplenial cortex (RSC) plays an important role in memory and spatial navigation. It shares functional similarities with the hippocampus, including the presence of place fields and lesion-induced impairments in spatial navigation, and the RSC is an important source of visual-spatial input to the hippocampus. Recently, the RSC has been the target of intense scrutiny among investigators of human memory and navigation. fMRI and lesion data suggest an RSC role in the ability to use landmarks to navigate to goal locations. However, no direct neurophysiological evidence of encoding navigational cues has been reported so the specific RSC contribution to spatial cognition has been uncertain. To examine this, we trained rats on a T-maze task in which the reward location was explicitly cued by a flashing light and we recorded RSC neurons as the rats learned. We found that RSC neurons rapidly encoded the light cue. Additionally, RSC neurons encoded the reward and its location, and they showed distinct firing patterns along the left and right trajectories to the goal. These responses may provide key information for goal-directed navigation, and the loss of these signals may underlie navigational impairments in subjects with RSC damage.

Network oscillatory activity driven by context memory processing is differently regulated by glutamatergic and cholinergic neurotransmission.

Memory retrieval requires coordinated intra- and inter-regional activity in networks of brain structures. Dysfunction of these networks and memory impairment are seen in many psychiatric disorders, but relatively little is known about how memory retrieval and memory failure are represented at the level of local and regional oscillatory activity. To address this question, we measured local field potentials (LFPs) from mice as they explored a novel context, retrieved memories for contextual fear conditioning, and after administration of two amnestic agents: the NMDA receptor antagonist MK-801 and muscarinic acetylcholine receptor antagonist scopolamine (SCOP). LFPs were simultaneously recorded from retrosplenial cortex (RSC), dorsal hippocampus (DH), and anterior cingulate cortex (ACC), which are involved in processing contextual memories, and analyzed for changes in intra-regional power and inter-regional peak coherence of oscillations across multiple frequency bands. Context encoding and memory retrieval sessions yielded similar patterns of changes across all three structures, including decreased delta power and increased theta peak coherence. Baseline effects of MK-801 and SCOP were primarily targeted to gamma oscillations, but in opposite directions. Both drugs also blocked memory retrieval, as indicated by reduced freezing when mice were returned to the conditioning context, but this common behavioral impairment was only associated with power and peak coherence disruptions after MK-801 treatment. These findings point to neural signatures for memory impairment, whose underlying mechanisms may serve as therapeutic targets for related psychiatric disorders.

The Long and the Short of It: Regiospecific Syntheses of Isomers of Dicarbomethoxydibenzo-27-crown-9 and Binding Abilities of Their Pyridyl Cryptands.

The two isomers 6 and 9 of cis(4,4'-)-dicarbomethoxydibenzo-27-crown-9 with tri- and tetra-(ethyleneoxy) linkages transposed were synthesized regiospecifically in high yields (94 and 92%, respectively) by the Wang-Pederson-Wessels (WPW) protocol and were converted via the corresponding diols 7 and 10 to the corresponding pyridyl cryptands 3 and 4 by reaction with pyridine-2,6-dicarbonyl chloride. As expected from Corey-Pauling-Koltun (CPK) models, the cryptand with the tri(ethyleneoxy) arm para to the ester linkages, "short-armed" cryptand 3, did display a higher binding constant (Ka = 2.4 × 105 M-1) with paraquats than the analogous dibenzo-30-crown-10-based cryptand previously studied; however, the effect was only twofold. Its binding to diquat was reduced by an order of magnitude (1.5 × 105 M-1), as expected on the basis of its narrower cavity. Also as expected, the cryptand with the tetra(ethyleneoxy) arm para to the ester linkages, "long-armed" cryptand 4, possessed diminished binding with both paraquats and diquat relative to the 30-crown-based analogue; in these systems, 2:1 H:G complexes were also detected by mass spectrometry. A crystal structure is reported for 3·DQ(PF6)2.

The Retrosplenial Cortical Role in Delayed Spatial Alternation.

The retrosplenial cortex (RSC) plays an important role in spatial cognition. RSC neurons exhibit a variety of spatial firing patterns and lesion studies have found that the RSC is necessary for spatial working memory tasks. However, little is known about how RSC neurons might encode spatial memory during a delay period. In the present study, we trained control rats and rats with excitotoxic lesions of the RSC on spatial alternation task with varying delay durations and in a separate group of rats, we recorded RSC neuronal activity as the rats performed the alternation task. We found that RSC lesions significantly impaired alternation performance, particularly at the longest delay duration. We also found that RSC neurons exhibited reliably different firing patterns throughout the delay periods preceding left and right trials, consistent with a working memory signal. These differential firing patterns were absent during the delay periods preceding errors. We also found that many RSC neurons exhibit a large spike in firing rate leading up to the start of the trial. Many of these trial start responses also differentiated left and right trials, suggesting that they could play a role in priming the 'go left' or 'go right' behavioral responses. Our results suggest that these firing patterns represent critical memory information that underlies the RSC role in spatial working memory.

Exercise accelerates place cell representational drift.

Stable neural ensembles are often thought to underlie stable learned behaviors and memory. Recent longitudinal experiments, however, that tracked the activity of the same neurons over days to weeks have shown that neuronal activity patterns can change over extended timescales even if behaviors remain the same - a phenomenon termed representational drift1. We have tested whether neural circuit remodeling, defined as any change in structural connectivity, contributes to representational drift. To do this, we tracked how hippocampal CA1 spatial representations of a familiar environment change with time in conventionally housed mice relative to mice housed with a running wheel. Voluntary exercise is an environmental stimulus that promotes hippocampal circuit remodeling, primarily via promoting adult neurogenesis in the dentate gyrus. Adult neurogenesis alters structural connectivity patterns, as the integration of adult-generated granule cells (abGCs) is a competitive process where new input-output synaptic connections may co-exist and/or even replace existing synaptic connections2. Comparing the spatial activity of downstream hippocampal CA1 place cells in the same familiar environment over two weeks, we found that the activity of place cells in exercise mice exhibited accelerated representational drift compared to control mice, suggesting that hippocampal circuit remodeling may indeed drive representational drift.

Emergence of a predictive model in the hippocampus.

The brain organizes experiences into memories that guide future behavior. Hippocampal CA1 population activity is hypothesized to reflect predictive models that contain information about future events, but little is known about how they develop. We trained mice on a series of problems with or without a common statistical structure to observe how memories are formed and updated. Mice that learned structured problems integrated their experiences into a predictive model that contained the solutions to upcoming novel problems. Retrieving the model during learning improved discrimination accuracy and facilitated learning. Using calcium imaging to track CA1 activity during learning, we found that hippocampal ensemble activity became more stable as mice formed a predictive model. The hippocampal ensemble was reactivated during training and incorporated new activity patterns from each training problem. These results show how hippocampal activity supports building predictive models by organizing new information with respect to existing memories.

Further clinical and molecular delineation of the 9q subtelomeric deletion syndrome supports a major contribution of EHMT1 haploinsufficiency to the core phenotype.

BACKGROUND: The 9q subtelomeric deletion syndrome (9qSTDS) is clinically characterised by moderate to severe mental retardation, childhood hypotonia and facial dysmorphisms. In addition, congenital heart defects, urogenital defects, epilepsy and behavioural problems are frequently observed. The syndrome can be either caused by a submicroscopic 9q34.3 deletion or by intragenic EHMT1 mutations leading to haploinsufficiency of the EHMT1 gene. So far it has not been established if and to what extent other genes in the 9q34.3 region contribute to the phenotype observed in deletion cases. This study reports the largest cohort of 9qSTDS cases so far. METHODS AND RESULTS: By a multiplex ligation dependent probe amplification (MLPA) approach, the authors identified and characterised 16 novel submicroscopic 9q deletions. Direct sequence analysis of the EHMT1 gene in 24 patients exhibiting the 9qSTD phenotype without such deletion identified six patients with an intragenic EHMT1 mutation. Five of these mutations predict a premature termination codon whereas one mutation gives rise to an amino acid substitution in a conserved domain of the protein. CONCLUSIONS: The data do not provide any evidence for phenotype-genotype correlations between size of the deletions or type of mutations and severity of clinical features. Therefore, the authors confirm the EHMT1 gene to be the major determinant of the 9qSTDS phenotype. Interestingly, five of six patients who had reached adulthood had developed severe psychiatric pathology, which may indicate that EHMT1 haploinsufficiency is associated with neurodegeneration in addition to neurodevelopmental defect.

Yield of modern genetic evaluation for patients with proximal hypospadias and descended gonads.

INTRODUCTION AND BACKGROUND: Although the pediatric urologic community has embraced a multidisciplinary genetic and endocrine evaluation for newborns with ambiguous genitalia, this approach has been reserved for the most severe cases of undervirilized 46,XY individuals despite growing evidence that genetic differences are found even in patients whose only genitourinary anomaly appears to be proximal hypospadias. Identifying these genetic differences is vital for counseling patients as they move through puberty to parenthood as well as parents on future pregnancies. OBJECTIVE: The primary objective was to evaluate genetic diagnosis in patients with proximal hypospadias. The authors hypothesized the more sensitive genetic evaluation available in the modern era will reveal a high rate of patients with proximal hypospadias and descended testicles who are found to have a genetic difference, supporting a thorough genetic evaluation in these patients. STUDY DESIGN: A retrospective review was performed of all patients who underwent surgical correction for proximal hypospadias at a single institution from January 1, 2010, to December 31, 2016. Those with midshaft hypospadias were excluded as were patients whose primary surgery was performed at an outside institution. Patient characteristics, including demographics, clinical presentation, genetic evaluation, and referral to a multidisciplinary difference of sex development (DSD) clinic, were collected. The chi-squared test and t-test were used for analysis. RESULTS: There were 112 patients with proximal hypospadias who met the inclusion criteria. Of these, 91 had bilaterally descended testicles, whereas 21 had one or more undescended testicles. Thirty-three percent of patients with isolated proximal hypospadias received genetic testing of some kind, with 24% seen in the multidisciplinary DSD clinic. Four patients had an associated genetic syndrome identified, and 5 had a genetic difference of unknown clinical significance. Overall, 10% of patients with proximal hypospadias and descended testicles had an identifiable genetic difference vs 33% with associated cryptorchidism. Of these, one patient with proximal hypospadias and descended testicles had a genetic difference of known clinical significance that was likely to have been missed in the absence of an evaluation by a geneticist. DISCUSSION AND CONCLUSION: There was a high rate of identifiable genetic differences in patients whose only genitourinary abnormality was proximal hypospadias, especially with the 1% risk of a likely missed diagnosis. These findings support the discussion of a genetic evaluation for all patients with proximal hypospadias, regardless of the testicular location.

Retrosplenial Cortical Representations of Space and Future Goal Locations Develop with Learning.

Recent findings suggest that long-term spatial and contextual memories depend on the retrosplenial cortex (RSC) [1-5]. RSC damage impairs navigation in humans and rodents [6-8], and the RSC is closely interconnected with brain regions known to play a role in navigation, including the hippocampus and anterior thalamus [9, 10]. Navigation-related neural activity is seen in humans [11] and rodents, including spatially localized firing [12, 13], directional firing [12, 14, 15], and responses to navigational cues [16]. RSC neuronal activity is modulated by allocentric, egocentric, and route-centered spatial reference frames [17, 18], consistent with an RSC role in integrating different kinds of navigational information [19]. However, the relationship between RSC firing patterns and spatial memory remains largely unexplored, as previous physiology studies have not employed behavioral tasks with a clear memory demand. To address this, we trained rats on a continuous T-maze alternation task and examined RSC firing patterns throughout learning. We found that the RSC developed a distributed population-level representation of the rat's spatial location and current trajectory to the goal as the rats learned. After the rats reached peak performance, RSC firing patterns began to represent the upcoming goal location as the rats approached the choice point. These neural simulations of the goal emerged at the same time that lesions impaired alternation performance, suggesting that the RSC gradually acquired task representations that contribute to navigational decision-making.

High-yielding, regiospecific synthesis of cis(4,4')-di(carbomethoxybenzo)-30-crown-10, its conversion to a pyridyl cryptand and strong complexation of 2,2'- and 4,4'-bipyridinium derivatives.

A high yielding (93%), regiospecific synthesis of cis(4,4')-di(carbomethoxybenzo)-30-crown-10 (1c) is reported. The derived crown ether diol 1d was converted to pyridyl cryptand 12 in 44% yield by reaction with pyridine-2,6-dicarbonyl chloride. Binding of two different 4,4'-bipyridinium (paraquat) species (3) and 2,2'-bipyridinium (diquat) 4 by 12 was explored via (1)H NMR spectroscopy, NOE experiments, mass spectrometry, X-ray crystallographic analyses, and isothermal titration calorimetry. Cryptand 12 exhibits the highest association constant for diquat ever reported (Ka = 1.9 x 10(6) M(-1)) and very high association constants for paraquats (Ka > 10(5) M(-1)) in acetone at 22 degrees C. The binding constant of diquat 4 by cryptand 12 is nearly 6-times higher than any other reported host.

A new functional bis(m-phenylene)-32-crown-10-based cryptand host for paraquats.

The pseudorotaxane complex of the new hydroxymethyl cryptand 3 with N,N'-dimethyl-4,4'-bipyridinium bis(hexafluorophosphate), PQ(PF6)2, has an association constant of 2.0(+/-0.3) x 10(4) M(-1). In the crystal structure of 3 x PQ(PF6)2 one of the bonding elements appears to be an aromatic edge-to-face interaction of a paraquat beta-proton with the hydroquinone moiety; this is the first time this interaction has been reported between a cryptand and paraquat.

The retrosplenial cortical role in encoding behaviorally significant cues.

The retrosplenial cortex (RSC) has recently begun to gain widespread interest because of its anatomical connectivity with other well-known memory structures, such as the hippocampus and anterior thalamus, and its role in spatial, contextual, and episodic memory. Although much of the current work on the RSC is focused on spatial cognition, there is also an extensive literature that shows that the RSC plays a critical role in a variety of conditioning tasks that have no obvious spatial component. Many of these studies suggest that the RSC is involved in identifying and encoding behaviorally significant cues, particularly those cues that predict reinforcement or the need for a behavioral response. Consistent with this idea, recent studies have shown that RSC neurons also encode cues in spatial navigation tasks. In this article, we review these findings and suggest that the encoding of cues is an important component of the RSC contribution to many forms of learning. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Memory: Ironing Out a Wrinkle in Time.

Individual hippocampal neurons encode time over seconds, whereas large-scale changes in population activity of hippocampal neurons encode time over minutes and days. New research shows how the hippocampus represents these multiple timescales simultaneously.

Cues, context, and long-term memory: the role of the retrosplenial cortex in spatial cognition.

Spatial navigation requires memory representations of landmarks and other navigation cues. The retrosplenial cortex (RSC) is anatomically positioned between limbic areas important for memory formation, such as the hippocampus (HPC) and the anterior thalamus, and cortical regions along the dorsal stream known to contribute importantly to long-term spatial representation, such as the posterior parietal cortex. Damage to the RSC severely impairs allocentric representations of the environment, including the ability to derive navigational information from landmarks. The specific deficits seen in tests of human and rodent navigation suggest that the RSC supports allocentric representation by processing the stable features of the environment and the spatial relationships among them. In addition to spatial cognition, the RSC plays a key role in contextual and episodic memory. The RSC also contributes importantly to the acquisition and consolidation of long-term spatial and contextual memory through its interactions with the HPC. Within this framework, the RSC plays a dual role as part of the feedforward network providing sensory and mnemonic input to the HPC and as a target of the hippocampal-dependent systems consolidation of long-term memory.

Self-injurious behavior vs. nonsuicidal self-injury: the CNS stimulant pemoline as a model of self-destructive behavior.

BACKGROUND: Historically, the field of self-injury has distinguished between the behaviors exhibited among individuals with a developmental disability (self-injurious behaviors; SIB) and those present within a normative population (nonsuicidal self-injury; NSSI),which typically result as a response to perceived stress. More recently, however, conclusions about NSSI have been drawn from lines of animal research aimed at examining the neurobiological mechanisms of SIB. Despite some functional similarity between SIB and NSSI, no empirical investigation has provided precedent for the application of SIB-targeted animal research as justification for pharmacological interventions in populations demonstrating NSSI. AIMS: The present study examined this question directly, by simulating an animal model of SIB in rodents injected with pemoline and systematically manipulating stress conditions in order to monitor rates of self-injury. METHODS: Sham controls and experimental animals injected with pemoline (200 mg/kg) were assigned to either a low stress (discriminated positive reinforcement) or high stress (discriminated avoidance) group and compared on the dependent measures of self-inflicted injury prevalence and severity. RESULTS: The manipulation of stress conditions did not impact the rate of self-injury demonstrated by the rats. The results do not support a model of stress-induced SIB in rodents. CONCLUSIONS: Current findings provide evidence for caution in the development of pharmacotherapies of NSSI in human populations based on CNS stimulant models. Theoretical implications are discussed with respect to antecedent factors such as preinjury arousal level and environmental stress.

Statistical and theoretical considerations for the platform re-location water maze.

The Morris water maze is a commonly employed method to investigate learning and memory. The task demands experimental subjects use distal spatial cues in navigating to a hidden escape platform while swimming in a pool of opaque water. Since its primary description thirty years ago, several modifications have emerged. For example, part-way through the experiment, the target platform can be re-located, thus requiring subjects re-learn spatial aspects of the task. This procedure demands sequential memory encoding of highly similar events and can be selectively impaired by genetic and pharmacological methods affecting cognitive flexibility. While the primary reasons for employing re-locating platform tasks are to study aspects of cognitive flexibility, the paradigms also demonstrate a potential for reducing within-treatment group variation by enabling within-subject analysis. We tested this hypothesis using the C57BL/6 mouse line, a commonly chosen subject for behavioral experiments, and demonstrate that a within-subject comparison approach is both valid and effective in reducing variability. Interestingly, the within-subject statistical advantage is most pronounced for performance measures of short-term memory. In addition, we find that subject naivety, but not experimental inter-phase interval or subcutaneous saline injections, has a significant effect on variation in performance. We also found repeated training in the Morris water maze improved short-term memory without enhancing long-term memory. Together, the data suggest platform re-location tasks can help alleviate within-group variability, a major conundrum in behavioral neuroscience, and provide valuable insight into the general sources of variability underlying performance in cognitive tasks.