Infantile Amnesia Is Related to Developmental Immaturity of the Maintenance Mechanisms for Long-Term Potentiation.

Infantile amnesia (IA) refers to the inability of adults to recall episodic memories from infancy or early childhood. While several hypotheses have been proposed to explain the occurrence of IA, the neurobiological and molecular bases for this accelerated forgetting phenomenon remain elusive. Using hippocampus-dependent object-location memory and contextual fear conditioning tasks, we confirmed that infant mice trained at postnatal day 20 (P20) displayed deficits in long-term memory retention compared to adult (P60) mice.

Conditional Deletion of Hippocampal CA2/CA3a Oxytocin Receptors Impairs the Persistence of Long-Term Social Recognition Memory in Mice.

Oxytocin (OXT) receptors (OXTRs) are prominently expressed in hippocampal CA2 and CA3 pyramidal neurons, but little is known about its physiological function. As the functional necessity of hippocampal CA2 for social memory processing, we tested whether CA2 OXTRs may contribute to long-term social recognition memory (SRM) formation. Here, we found that conditional deletion of from forebrain () or CA2/CA3a-restricted excitatory neurons in adult male mice impaired the persistence of long-term SRM but had no effect on sociability and preference for social novelty.

Oxytocin stimulates hippocampal neurogenesis via oxytocin receptor expressed in CA3 pyramidal neurons.

In addition to the regulation of social and emotional behaviors, the hypothalamic neuropeptide oxytocin has been shown to stimulate neurogenesis in adult dentate gyrus; however, the mechanisms underlying the action of oxytocin are still unclear. Taking advantage of the conditional knockout mouse model, we show here that endogenous oxytocin signaling functions in a non-cell autonomous manner to regulate survival and maturation of newly generated dentate granule cells in adult mouse hippocampus via oxytocin receptors expressed in CA3 pyramidal neurons. Through bidirectional chemogenetic manipulations, we also uncover a significant role for CA3 pyramidal neuron activity in regulating adult neurogenesis in the dentate gyrus.

Neonatal Dexamethasone Treatment Exacerbates Hypoxia/Ischemia-Induced White Matter Injury.

Dexamethasone, a synthetic glucocorticoid, has been widely used to prevent or ameliorate morbidity of chronic lung disease in preterm infants with respiratory distress syndrome. Despite its beneficial effect on neonatal lung function, growing concern has arisen about adverse effects of this clinical practice on fetal brain development. We demonstrated previously that neonatal dexamethasone (DEX) treatment may render the newborn brain to be more vulnerable to hypoxia/ischemia (HI)-induced gray matter injury.

Conditional deletion of Eps8 reduces hippocampal synaptic plasticity and impairs cognitive function.

Epidermal growth factor receptor substrate 8 (Eps8) is a multifunctional protein involved in actin cytoskeleton regulation and is abundantly expressed in many brain regions. However, the functional significance of Eps8 in the brain has only just begun to be elucidated. Here, we demonstrate that genetic deletion of Eps8 (Eps8) from excitatory neurons leads to impaired performance in a novel object recognition test.

Alleviating Bone Cancer-induced Mechanical Hypersensitivity by Inhibiting Neuronal Activity in the Anterior Cingulate Cortex.

Background: The anterior cingulate cortex (ACC) is a brain region that has been critically implicated in the processing of pain perception and modulation. While much evidence has pointed to an increased activity of the ACC under chronic pain states, less is known about whether pain can be alleviated by inhibiting ACC neuronal activity.

Methods: The authors used pharmacologic, chemogenetic, and optogenetic approaches in concert with viral tracing technique to address this issue in a mouse model of bone cancer-induced mechanical hypersensitivity by intratibia implantation of osteolytic fibrosarcoma cells.

Early life stress dampens stress responsiveness in adolescence: Evaluation of neuroendocrine reactivity and coping behavior.

Stressful experiences during early life (ELS) can affect brain development, thereby exerting a profound and long-lasting influence on mental development and psychological health. The stress inoculation hypothesis presupposes that individuals who have early experienced an attenuated form of stressors may gain immunity to its more virulent forms later in life. Increasing evidence demonstrates that ELS may promote the development of subsequent stress resistance, but the mechanisms underlying such adaptive changes are not fully understood.

Acute food deprivation enhances fear extinction but inhibits long-term depression in the lateral amygdala via ghrelin signaling.

Fear memory-encoding thalamic input synapses to the lateral amygdala (T-LA) exhibit dynamic efficacy changes that are tightly correlated with fear memory strength. Previous studies have shown that auditory fear conditioning involves strengthening of synaptic strength, and conversely, fear extinction training leads to T-LA synaptic weakening and occlusion of long-term depression (LTD) induction. These findings suggest that the mechanisms governing LTD at T-LA synapses may determine the behavioral outcomes of extinction training.

Chronic Social Stress Affects Synaptic Maturation of Newly Generated Neurons in the Adult Mouse Dentate Gyrus.

Background: Chronic stress has been found to suppress adult neurogenesis, but it remains unclear whether it may affect the maturation process of adult-born neurons. Here, we examined the influence of chronic social defeat stress on the morphological and electrophysiological properties of adult-born dentate granule cells at different developmental stages.

Methods: Adult C57BL/6 mice were subjected to 10 days of chronic social defeat stress followed by a social interaction test 24 hours after the last defeat.

The phospholipid-binding protein SESTD1 negatively regulates dendritic spine density by interfering with Rac1-Trio8 signaling pathway.

Dendritic spines are actin-rich protrusions from neuronal dendrites that harbor the majority of excitatory synapses. The balance of spine formation and retraction may influence dendritic integrity. While knowledge of the molecular mechanisms that promote dendritic spine formation has accumulated, little is known about the factors that limit spine formation.

Cocaine Withdrawal Impairs mGluR5-Dependent Long-Term Depression in Nucleus Accumbens Shell Neurons of Both Direct and Indirect Pathways.

We previously reported that animals withdrawn from repeated cocaine exposure exhibited a selective deficit in the ability to elicit metabotropic glutamate receptor 5 (mGluR5)-dependent long-term depression (LTD) in the nucleus accumbens (NAc) shell. To determine whether such impairment occurs in the NAc in a cell-type-specific manner, we used bacterial artificial chromosome (BAC) transgenic mice expressing enhanced green fluorescent protein (eGFP) under the control of gene regulatory elements for the dopamine D1 receptor (Drd1) or dopamine D2 receptor (Drd2) to identify distinct subpopulations of medium spiny neurons (MSNs). We found that bath application of group I mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG) reliably induced LTD in both NAc shell and core MSNs of wild-type, hemizygous Drd1-eGFP, and Drd2-eGFP mice.

Acute hypernatremia dampens stress-induced enhancement of long-term potentiation in the dentate gyrus of rat hippocampus.

Stress often occurs within the context of homeostatic threat, requiring integration of physiological and psychological demands to trigger appropriate behavioral, autonomic and endocrine responses. However, the neural mechanism underlying stress integration remains elusive. Using an acute hypernatremic challenge (2.

Brain-derived neurotrophic factor in the amygdala mediates susceptibility to fear conditioning.

Fear conditioning in animals has been used extensively to model clinical anxiety disorders. While individual animals exhibit marked differences in their propensity to undergo fear conditioning, the physiologically relevant mediators have not yet been fully characterized. Here, we demonstrate that C57BL/6 inbred mouse strain subjected to a regimen of chronic social defeat stress (CSDS) can be separated into susceptible and resistant subpopulations that display different levels of fear responses in an auditory fear conditioning paradigm.

Long-term potentiation at excitatory synaptic inputs to the intercalated cell masses of the amygdala.

The intercalated cell masses (ITCs) of the amygdala are clusters of GABAergic interneurons that surround the basolateral complex of the amygdala. ITCs have been increasingly implicated in the acquisition and extinction of conditioned fear responses, but the underlying cellular mechanisms remain unexplored. Here, we report that repetitive stimulation of lateral amygdala (LA) afferents with a modified theta burst stimulation (TBS) protocol and induces long-term potentiation (LTP) of excitatory synapses onto medial paracapsular ITC (Imp) neurons.

Cell type-specific expression of Eps8 in the mouse hippocampus.

Background: Epidermal growth factor receptor substrate 8 (Eps8) is a multifunctional protein that regulates actin cytoskeleton dynamics and architecture through its barbed-end capping and bundling activities. In cultured hippocampal neurons, Eps8 is enriched at dendritic spine heads and is required for spine morphogenesis; however, the detailed expression pattern of Eps8 in the hippocampus has not yet been explored.

Results: Here, we demonstrate that endogenous Eps8 protein is restrictively expressed in neurons (NeuN-positive), but not in glial cells (glial fibrillary acidic protein-positive) in area CA1 of the mouse hippocampus.

Neonatal dexamethasone treatment exacerbates hypoxic-ischemic brain injury.

Background: The synthetic glucocorticoid dexamethasone (DEX) is commonly used to prevent chronic lung disease in prematurely born infants. Treatment regimens usually consist of high doses of DEX for several weeks, notably during a critical period of brain development. Therefore, there is some concern about adverse effects of this clinical practice on fetal brain development.

A single in vivo cocaine administration impairs 5-HT(1B) receptor-induced long-term depression in the nucleus accumbens.

The nucleus accumbens (NAc) is a crucial forebrain nucleus implicated in reward-based decision-making. While NAc neurons are richly innervated by serotonergic fibers, information on the functional role of serotonin 5-hydroxytryptamine (5-HT) in the NAc is still sparse. Here, we demonstrate that brief application of 5-HT or 5-HT1B receptor agonist CP 93129 induced a long-term depression (LTD) of glutamatergic transmission in NAc neurons.

Oxytocin promotes long-term potentiation by enhancing epidermal growth factor receptor-mediated local translation of protein kinase Mζ.

In addition to triggering the birthing process and milk release, the hypothalamic neuropeptide oxytocin (OXT) plays an important role in the regulation of complex social cognition and behavior. Previous work has shown that OXT can regulate hippocampal synaptic plasticity and improve hippocampus-dependent cognitive functions in the female mice, but the underlying mechanisms remain largely unclear. Here, we demonstrate that OXT promotes the maintenance of long-term potentiation (LTP) induced by one train of tetanic stimulation (TS) in the CA1 region of hippocampal slices from both nulliparous female and male rats through a previously unknown mechanism involving OXT receptor (OXTR)-dependent and epidermal growth factor receptor (EGFR)-mediated local translation of an atypical protein kinase C isoform, protein kinase Mζ (PKMζ), in dendrites.

Vascular endothelial growth factor-dependent spinogenesis underlies antidepressant-like effects of enriched environment.

Current antidepressant treatments remain limited by poor efficacy and a slow onset of action. Increasing evidence demonstrates that enriched environment (EE) treatment can promote structural and behavioral plasticity in the brain and dampen stress-induced alterations of neuroplasticity. Here, we have examined whether short term exposure to EE is able to produce antidepressant-like effects.

Activation of NMDA receptors reduces metabotropic glutamate receptor-induced long-term depression in the nucleus accumbens via a CaMKII-dependent mechanism.

Glutamate is the major excitatory neurotransmitter in the brain and exerts its actions through two distinct types of receptors, ionotropic and metabotropic glutamate receptors (mGluR). Although functional interplay between ionotropic N-methyl-d-aspartate receptors (NMDAR) and mGluR has been convincingly demonstrated in native and recombinant systems, the mechanism by which NMDAR activation leads to modulation of mGluR function has yet to be elucidated. Using whole-cell patch-clamp recordings in mouse nucleus accumbens (NAc) slices, we found that tetanic stimulation (TS) of excitatory afferents with a naturally occurring frequency (10 min at 13 Hz) reliably induces a mGluR1/5-dependent long-term depression (mGluR1/5-LTD) of excitatory synaptic transmission.

Impairment of long-term depression in the anterior cingulate cortex of mice with bone cancer pain.

The anterior cingulate cortex (ACC) has been shown to play an important role in pain-related perception and chronic pain. However, little is known about the molecular mechanisms involved. To address this issue, we analyzed excitatory synaptic transmission and long-term synaptic plasticity in layer II/III pyramidal neurons within the rostral ACC (rACC) from mice with bone cancer pain induced by intra-tibia implantation of osteolytic fibrosarcoma cells.

A critical role for protein tyrosine phosphatase nonreceptor type 5 in determining individual susceptibility to develop stress-related cognitive and morphological changes.

While stressful life events confer increased risk for the development of psychopathology, most individuals experiencing adversity maintain normal psychological functioning, suggesting that individual differences may influence the susceptibility to develop stress-related psychiatric disorders. However, little is known about what determines this difference between individuals at the molecular level. In the present study, we identify that protein tyrosine phosphatase nonreceptor type 5 (PTPN5) (also known as STEP) is a critical determinant of differences in individual susceptibility to develop stress-related cognitive and morphological changes in rats.

Sex difference in stress-induced enhancement of hippocampal CA1 long-term depression during puberty.

Females and males react differently to stress. Our previous studies revealed that acute stress facilitates the induction of long-term depression (LTD) in hippocampal CA1 region. However, it remains unknown whether sex difference exists in the effect of stress on LTD.

Prenatal stress alters hippocampal synaptic plasticity in young rat offspring through preventing the proteolytic conversion of pro-brain-derived neurotrophic factor (BDNF) to mature BDNF.

Prenatal stress (PS) has been associated with a higher risk of development of various neurological and psychiatric disorders later in life, but the underlying mechanisms are not yet fully understood. Here, using a chronic prenatal restraint stress model where the rat dams were immobilized for 45 min three times per day during the last week of pregnancy, we explored the long-lasting effects of PS on hippocampal synaptic plasticity in the offspring of both sexes. We found that PS switched the direction of synaptic plasticity in hippocampal CA1 region, favouring low-frequency stimulation-induced long-term depression (LTD) and opposing the induction of long-term potentiation (LTP) by high-frequency stimulation in young (5-week-old) rat offspring, but these changes disappeared at adult age (8 weeks old).

Insulin promotes dendritic spine and synapse formation by the PI3K/Akt/mTOR and Rac1 signaling pathways.

Insulin and its receptor are broadly expressed throughout the brain and have been postulated to play a crucial role in synaptic plasticity. Although structural remodeling of dendritic spines is associated with stable expression of synaptic plasticity, the role of insulin receptor (IR) signaling in the establishment and dynamic changes of dendritic spines remains unclear. Here we report that insulin promotes dendritic spine formation in primary cultures of rat hippocampal neurons.