Volume 20 Issue 11, November 2017

The hippocampus serves a critical function in memory, navigation, and cognition. Nature Neuroscience asked John Lisman to lead a group of researchers in a dialog on shared and distinct viewpoints on the hippocampus.

Moser, Moser and McNaughton provide a historical overview describing how ideas about integration of self-motion cues have shaped our understanding of spatial representation in hippocampal–entorhinal systems, from the discovery of place cells in the 1970s to contemporary studies of spatial coding in intermingled and interacting cell types within complex circuits.

Considerable progress has been made in understanding how the brain encodes our sense of direction. This Perspective considers the link between self-motion detection and navigation circuits and discusses future challenges for establishing the neural mechanisms responsible for sensing direction in both real-world and virtual-reality environments.

In this Perspective, the authors propose that functional insights into generalist cortical computation may reside at the level of population patterns rather than functionally defined cell types. They then review results showing that medial entorhinal cortex (MEC) neurons exhibit substantial heterogeneity, suggesting MEC is a generalist circuit that computes diverse episodic states.

Synaptic integration is critical for determining how information in the brain is encoded, stored and retrieved. The authors review roles for synaptic integrative mechanisms in the selection, generation and plasticity of spatially modulated firing, and in related temporal codes for representation of space.

Distinct processing of objects and space has been an organizing principle for studying higher-level vision and medial temporal lobe memory. Here Connor and Knierim discuss instead how spatial information, on both local and global scales, is deeply integrated into the ventral-temporal object-processing pathway in vision and memory.

Cognitive maps are internal representations of large-scale navigable spaces. While they have been long studied in rodents, recent work in humans reveals new insights into how cognitive maps are encoded, anchored to environmental landmarks and used to plan routes. Similar neural mechanisms might be used to form ‘maps’ of nonphysical spaces.

Mouse models have generally failed to recapitulate the dopaminergic neurodegeneration seen in Parkinson's disease. Expressing mutant α-synuclein in a background of elevated dopamine generates mice with nigrostriatal degeneration.

The discovery of a circuit from the midcingulate cortex to the posterior insula that is essential for cortical sensitization sheds light on the plasticity mechanisms responsible for the transition from acute to chronic pain.

Physiological and optogenetic dissection of discrete locus coeruleus neuronal populations reveals a functional disassociation, with heterogeneous engagement of locus coeruleus neurons in either fear learning or extinction models.

Long-range enhancer interactions regulate gene expression, yet how they influence CNS development and disease remains unclear. Glasgow et al. identified glia-specific elements and 3D chromatin architectures regulating NFIA expression during development. They also found that deletion of these enhancers suppresses NFIA expression and tumorigenesis in an in vivo glioma model.

The mechanisms of gliotransmitter release and their impact on neuronal signaling have remained largely elusive. The authors describe two functionally non-overlapping v-SNARE-dependent astrocytic release pathways that oppositely control synaptic strength at presynaptic sites. Thus, astrocytes are able to fine-tune fast glutamatergic neurotransmission and control fundamental processes of synaptic communication.

Astrocytes differentially regulate excitatory and inhibitory synaptic transmission in the CeM, the major output nucleus of the amygdala. Astrocytes thereby reduce neuronal activity in the CeM and diminish fear expression in vivo. Therefore, astrocytes influence neural network activity and animal behavior through the regulation of specific synapses.

Spinal cord injury causes life-threatening infections. The authors report that this is partially mediated by a maladaptive neuroendocrine reflex, extending from the spinal cord to the adrenal glands, where it blocks catecholamines while producing immunosuppressive corticosteroids. The effect depends on the spinal injury level, and normalization of hormones production by the adrenals rescued mice from pneumonia.

Dopamine has long been thought to contribute to neurodegeneration in Parkinson's disease. The authors show that dopamine-induced neuron death in the substantia nigra is dependent on α-synuclein and coincides with increased levels of α-synuclein oligomers. The results suggest a synergistic interaction between dopamine and α-synuclein that underlies neuronal vulnerability in disease.

The precise underpinnings of Parkinson's disease and other disorders associated with the accumulation of α-synuclein are unclear. This study shows that PrP^C mediates α-synuclein-associated synaptic dysfunction and memory deficits. Blocking specific events in receptor biology rescued cognitive deficits in mice, suggesting new possibilities for intervention in synucleinopathies.

Esr1⁺ cells in the VMHvl are well known to influence female sexual behaviors. Here the authors find a surprising new role of this population in female aggression. They further reveal that the female VMHvl contains two molecularly and anatomically distinct subdivisions: one for aggression and one for sex.

The authors identify the midcingulate cortex as a region that gates nociceptive plasticity without modulating basal nociception or the affective component of acute pain in mice. They identify a novel pathway from the midcingulate cortex to the posterior insula that recruits descending serotonergic projections to facilitate nociception.

A small population of brainstem noradrenaline neurons powerfully modulates global brain function, but how they regulate diverse—and at times opposing—functions is not clear. The authors report that a modular organization in this neuromodulatory system, coupled with context-dependent activation modes, controls the balance between opposing emotional and flexible learning states.

Using two-photon Ca²⁺ imaging in hippocampal area CA1 of Df(16)A^+/− mice, an animal model of 22q11.2 deletion syndrome, the authors found a reduction in spatial map stability compared to that in wild-type mice, as well as an absence of goal-directed place cell reorganization during goal-oriented spatial learning.

Davis et al. report that fear memories can be critically regulated by parvalbumin-expressing interneurons in the basolateral amygdala. Silencing these interneurons following fear memory extinction caused a reemergence of fear expression that was accompanied by increased activation of fear-encoding neurons and fear-associated 3–6 Hz oscillations within a basolateral amygdala–prefrontal cortex circuit.

Girardeau et al. show that coordinated reactivations of functionally connected neurons between the hippocampus and the basolateral amygdala occur during sharp wave–ripples of sleep following training on an aversive spatial task. These findings suggest a mechanism by which emotional memories are consolidated during sleep.

The authors show how predictive representations are useful for maximizing future reward, particularly in spatial domains. They develop a predictive-map model of hippocampal place cells and entorhinal grid cells that captures a wide variety of effects from human and rodent literature.