ABSTRACT
The hippocampus is critical for the acquisition and retrieval of episodic and contextual memories. Lesions of the dentate gyrus, a principal input of the hippocampus, block memory acquisition, but it remains unclear whether this region also plays a role in memory retrieval. Here we combine cell-type specific neural inhibition with electrophysiological measurements of learning-associated plasticity in behaving mice to demonstrate that dentate gyrus granule cells are not required for memory retrieval, but instead have an unexpected role in memory maintenance. Furthermore, we demonstrate the translational potential of our findings by showing that pharmacological activation of an endogenous inhibitory receptor expressed selectively in dentate gyrus granule cells can induce a rapid loss of hippocampal memory. These findings open a new avenue for the targeted erasure of episodic and contextual memories.
Subject(s)
Dentate Gyrus/cytology , Memory/physiology , Neurons/cytology , Adenosine/metabolism , Animals , Conditioning, Psychological , Entorhinal Cortex/physiology , Female , Male , Mice, Inbred C57BL , Mice, Transgenic , Models, Biological , Neuronal Plasticity , Receptors, Neuropeptide Y/metabolism , Signal Transduction , Synaptic Transmission/physiologyABSTRACT
The amygdala has been shown to be essential for the processing of acute and learned fear across animal species. However, the downstream neural circuits that mediate these fear responses differ according to the nature of the threat, with separate pathways having been identified for predator, conspecific and physically harmful threats. In particular, the dorsomedial part of the ventromedial hypothalamus (VHMdm) is critical for the expression of defensive responses to predators. Here, we tested the hypothesis that this circuit also participates in predator fear memory by transient pharmacogenetic inhibition of the VMHdm and its downstream effector, the dorsal periaqueductal grey, during predator fear learning in the mouse. Our data demonstrate that neural activity in the VMHdm is required for both the acquisition and recall of predator fear memory, whereas that of its downstream effector, the dorsal periaqueductal grey, is required only for the acute expression of fear. These findings are consistent with a role for the medial hypothalamus in encoding an internal emotional state of fear.
Subject(s)
Fear/physiology , Learning/physiology , Mental Recall/physiology , Ventromedial Hypothalamic Nucleus/physiology , Animals , Female , Male , Mice , Mice, Inbred C57BL , Neural Pathways/physiology , Periaqueductal Gray/physiologyABSTRACT
Mutations in cyclin-dependent kinase-like 5 (CDKL5) cause early-onset epileptic encephalopathy, a neurodevelopmental disorder with similarities to Rett Syndrome. Here we describe the physiological, molecular, and behavioral phenotyping of a Cdkl5 conditional knockout mouse model of CDKL5 disorder. Behavioral analysis of constitutive Cdkl5 knockout mice revealed key features of the human disorder, including limb clasping, hypoactivity, and abnormal eye tracking. Anatomical, physiological, and molecular analysis of the knockout uncovered potential pathological substrates of the disorder, including reduced dendritic arborization of cortical neurons, abnormal electroencephalograph (EEG) responses to convulsant treatment, decreased visual evoked responses (VEPs), and alterations in the Akt/rpS6 signaling pathway. Selective knockout of Cdkl5 in excitatory and inhibitory forebrain neurons allowed us to map the behavioral features of the disorder to separable cell-types. These findings identify physiological and molecular deficits in specific forebrain neuron populations as possible pathological substrates in CDKL5 disorder.
Subject(s)
Disease Models, Animal , Phenotype , Prosencephalon/pathology , Protein Serine-Threonine Kinases/genetics , Rett Syndrome/genetics , Rett Syndrome/pathology , Signal Transduction/physiology , Spasms, Infantile/genetics , Spasms, Infantile/pathology , Analysis of Variance , Animals , Blotting, Western , Dendrites/pathology , Electroencephalography , Epileptic Syndromes , Evoked Potentials, Visual/physiology , Eye Movements/physiology , Fluorescent Antibody Technique , Immunohistochemistry , Mice , Mice, Knockout , Reverse Transcriptase Polymerase Chain Reaction , Statistics, NonparametricABSTRACT
The neural circuits mediating fear to naturalistic threats are poorly understood. We found that functionally independent populations of neurons in the ventromedial hypothalamus (VMH), a region that has been implicated in feeding, sex and aggression, are essential for predator and social fear in mice. Our results establish a critical role for VMH in fear and have implications for selective intervention in pathological fear in humans.
