The hippocampus plays an essential role in learning. Each of the three major hippocampal subfields, dentate gyrus (DG), CA3, and CA1, has a unique function in memory formation and consolidation, and also exhibit distinct local field potential (LFP) signatures during memory consolidation processes in non-rapid eye movement (NREM) sleep. The classic LFP events of the CA1 region, sharp-wave ripples (SWRs), are induced by CA3 activity and considered to be an electrophysiological biomarker for episodic memory. In LFP recordings along the dorsal CA1-DG axis from sleeping male mice, we detected and classified two types of LFP events in the DG: high-amplitude dentate spikes (DSs), and a novel event type whose current source density (CSD) signature resembled that seen during CA1 SWR, but which, most often, occurred independently of them. Because we hypothesize that this event type is similarly induced by CA3 activity, we refer to it as dentate sharp wave (DSW). We show that both DSWs and DSs differentially modulate...

The nucleus accumbens shell (NAcSh) regulates emotional and motivational responses, a function mediated, in part, by integrating and prioritizing extensive glutamatergic projections from limbic and paralimbic brain regions. Each of these inputs is thought to encode unique aspects of emotional and motivational arousal. The projections do not operate alone, but rather are often activated simultaneously during motivated behaviors, during which they can interact and coordinate in shaping behavioral output. To understand the anatomic and physiological bases underlying these interprojection interactions, the current study in mice of both sexes focused on how the basolateral amygdala projection (BLAp) to the NAcSh regulates, and is regulated by, projections from the medial prefrontal cortex (mPFCp) and paraventricular nucleus of the thalamus (PVTp). Using a dual-color SynaptoTag technique combined with a backfilling spine imaging strategy, we found that all three afferent projections primarily targeted the second...

Endurance represents a highly adaptive function of fear memory and a major cause of maladaptive fear- and anxiety-related mental disorders. However, less is known about the mechanisms underlying the persistence of fear memory. The epigenetic gene regulation recently emerged as an important mechanism for memory persistence. In the previous study, we found that BAF53b, a neuron-specific subunit of BAF chromatin remodeling complex, is induced after auditory cued fear conditioning in the lateral amygdala (LA) and is crucial for recent fear memory formation. In this study using mice of both sexes, we report a delayed induction of BAF53b in the LA 48 h after auditory fear conditioning and its critical role for the persistence of established fear memory. To specifically block the delayed but not the early induced BAF53b function, we used a postlearning knock-down method based on RNAi. The transient knockdown of Baf53b using siRNA in the lateral amygdala 24 h after cued fear conditioning led to specific impairment...

Conditional gene inactivation and restoration are powerful tools for studying gene functions in the nervous system and for modeling neuropsychiatric diseases. The combination of the two is necessary to interrogate specific cell types within defined developmental stages. However, very few methods and animal models have been developed for such purpose. Here we present a versatile method for conditional gene inactivation and in situ restoration through reversibly inverting a critical part of its endogenous genomic sequence by Cre- and Flp-mediated recombinations. Using this method, we generated a mouse model to manipulate Mecp2 , an X-linked dosage-sensitive gene whose mutations cause Rett syndrome. Combined with multiple Cre- and Flp-expressing drivers and viral tools, we achieved efficient and reliable Mecp2 inactivation and restoration in the germline and several neuronal cell types, and demonstrated phenotypic reversal and prevention on cellular and behavioral levels in male mice. This study not only prov...

In the article “Somatostatin-Expressing Interneurons in the Auditory Cortex Mediate Sustained Suppression by Spectral Surround,” by Anna A. Lakunina, Matthew B. Nardoci, Yashar Ahmadian, and Santiago Jaramillo, which appeared on pages [3564–3575][1] of the April 29, 2020 issue, the authors

In the article “Relating Divisive Normalization to Neuronal Response Variability” by Ruben Coen-Cagli and Selina S. Solomon, which appeared on pages [7344–7356][1] of the September 11, 2019 issue, the authors report an error in Materials and Methods in Equations 1.11–1.13, concerning the

Many clinical and preclinical studies report higher prevalence and severity of chronic pain in females. We used hyperalgesic priming with interleukin 6 (IL-6) priming and PGE2 as a second stimulus as a model for pain chronicity. Intraplantar IL-6 induced hypersensitivity was similar in magnitude and duration in both males and females, while both paw and intrathecal PGE2 hypersensitivity was more persistent in females. This difference in PGE2 response was dependent on both circulating estrogen and translation regulation signaling in the spinal cord. In males, the duration of hypersensitivity was regulated by testosterone. Since the prolactin receptor (Prlr) is regulated by reproductive hormones and is female-selectively activated in sensory neurons, we evaluated whether Prlr signaling contributes to hyperalgesic priming. Using ΔPRL, a competitive Prlr antagonist, and a mouse line with ablated Prlr in the Nav1.8 sensory neuronal population, we show that Prlr in sensory neurons is necessary for the developmen...

One emerging concept in neuroscience states that synaptic vesicles and the molecular machinery underlying spontaneous transmitter release are different from those underlying action potential-driven synchronized transmitter release. Differential neuromodulation of these two distinct release modes by metabotropic glutamate receptors (mGluRs) constitutes critical supporting evidence. However, the mechanisms underlying such a differential modulation are not understood. Here, we investigated the mechanisms of the modulation by group I mGluRs (mGluR Is) on spontaneous glutamate release in the medial nucleus of the trapezoid body (MNTB), an auditory brainstem nucleus critically involved in sound localization. Whole-cell patch recordings from brainstem slices of mice of both sexes were performed. Activation of mGluR I by 3,5-dihydroxyphenylglycine (3,5-DHPG; 200 μm) produced an inward current at −60 mV and increased spontaneous glutamate release in MNTB neurons. Pharmacological evidence indicated involvement of bo...

Skilled forelimb movements are initiated by feedforward motor commands conveyed by supraspinal motor pathways. The accuracy of reaching and grasping relies on internal feedback pathways that update ongoing motor commands. In mice lacking the axon guidance molecule EphA4, axonal misrouting of the corticospinal tract and spinal interneurons is manifested, leading to a hopping gait in hindlimbs. Moreover, mice with a conditional forebrain deletion of EphA4, display forelimb hopping in adaptive locomotion and exploratory reaching movements. However, it remains unclear how loss of EphA4 signaling disrupts function of forelimb motor circuit and skilled reaching and grasping movements. Here we investigated how neural circuits controlling skilled reaching were affected by the loss of EphA4. Both male and female C57BL/6 wild-type, heterozygous EphA4+/−, and homozygous EphA4−/− mice were used in behavioral and in vivo electrophysiological investigations. We found that EphA4 knock-out (−/−) mice displayed impaired go...

The ability to see movement is one of the most survival-critical and evolutionarily ancient abilities of animal vision. Yet our perception of motion, like our perception of other visual features, is subject to illusions and biases. For example, when a diagonally striped “barber pole” rotates to