Consolidation Of Recognition Memory Research Articles

Complement C5a receptor 1 blockade reverses cognitive deficits following cranial radiation therapy for brain cancer.

Cranial radiation therapy (RT) for brain cancers leads to an irreversible decline in cognitive function without an available remedy. Radiation-induced cognitive deficits (RICD) are particularly a pressing problem for the survivors of pediatric and low grade glioma (LGG) patients who often live long post-RT. Radiation-induced elevated neuroinflammation and gliosis, triggered by the detrimental CNS complement cascade, lead to excessive synaptic and cognitive loss. Using intact and brain cancer-bearing mouse models, we now show that targeting anaphylatoxin complement C5a receptor (C5aR1) is neuroprotective against RICD. We used a genetic knockout, C5aR1 KO mouse, and a pharmacologic approach, employing the orally active, brain penetrant C5aR1 antagonist PMX205, to reverse RICD. Irradiated C5aR1 KO and WT mice receiving PMX205 showed significant neurocognitive improvements in object recognition memory and memory consolidation tasks. C5aR1 inhibition reduced microglial activation, astrogliosis, and synaptic loss in the irradiated brain. Importantly, C5aR1 inhibition in the syngeneic, orthotopic astrocytoma, and glioblastoma-bearing mice protected against RICD without interfering with the therapeutic efficacy of RT to reduce tumor volume in vivo . PMX205 is currently in clinical trials for amyotrophic lateral sclerosis (ALS). Thus, C5aR1 inhibition is a translationally feasible approach to address RICD, an unmet medical need.

Double dissociation of perirhinal nicotinic acetylcholine receptors and dopamine D2 receptors in modulation of object memory consolidation by nicotine, cocaine and their conditioned stimuli

There are indications that drug conditioned stimuli (CS) may activate neurochemical systems of memory modulation that are activated by the drugs themselves. To directly test this hypothesis, a cholinergic nicotinic receptor antagonist (mecamylamine; MEC: 0, 10 or 30 µg/side) and a dopamine D2 receptor antagonist (l-741,626: 0, 0.63, 2.5 µg/side) were infused in the perirhinal cortex (PRh) to block modulation of object recognition memory consolidation induced by 0.4 mg/kg nicotine, 20 mg/kg cocaine, or their CSs. To establish these CSs, male Sprague-Dawley rats were confined for 2 h in a chamber, the CS+, after injections of 0.4 mg/kg nicotine, or 20 mg/kg cocaine, and in another chamber, the CS−, after injections of vehicle. This was repeated over 10 days (5 drug/CS+ and 5 vehicle/CS− pairings in total). It was found that the memory enhancing action of post-sample nicotine was blocked by intra-PRh infusions of both MEC doses, and 30 µg/side MEC also blocked the memory enhancing action of the nicotine CS. Interestingly, intra-PRh MEC did not block the memory enhancing effect of cocaine, nor that of the cocaine CS. In contrast, the memory enhancing action of post-sample cocaine administration was blocked by both l-741,626 doses, and 2.5 µg/side also blocked the effect of the cocaine CS, but not the memory effects of nicotine or of the nicotine CS. This functional double dissociation strongly indicates that drug CSs modulate memory consolidation by activating neural systems that are activated by the drugs themselves.

Noradrenergic consolidation of social recognition memory is mediated by β-arrestin–biased signaling in the mouse prefrontal cortex

Social recognition memory (SRM) is critical for maintaining social relationships and increasing the survival rate. The medial prefrontal cortex (mPFC) is an important brain area associated with SRM storage. Norepinephrine (NE) release regulates mPFC neuronal intrinsic excitability and excitatory synaptic transmission, however, the roles of NE signaling in the circuitry of the locus coeruleus (LC) pathway to the mPFC during SRM storage are unknown. Here we found that LC-mPFC NE projections bidirectionally regulated SRM consolidation. Propranolol infusion and β-adrenergic receptors (β-ARs) or β-arrestin2 knockout in the mPFC disrupted SRM consolidation. When carvedilol, a β-blocker that can mildly activate β-arrestin-biased signaling, was injected, the mice showed no significant suppression of SRM consolidation. The impaired SRM consolidation caused by β1-AR or β-arrestin2 knockout in the mPFC was not rescued by activating LC-mPFC NE projections; however, the impaired SRM by inhibition of LC-mPFC NE projections or β1-AR knockout in the mPFC was restored by activating the β-arrestin signaling pathway in the mPFC. Furthermore, the activation of β-arrestin signaling improved SRM consolidation in aged mice. Our study suggests that LC-mPFC NE projections regulate SRM consolidation through β-arrestin-biased β-AR signaling.

Dopamine D1/D5 Receptors in the Retrosplenial Cortex Are Necessary to Consolidate Object Recognition Memory.

The retrosplenial cortex (RSC) has been widely related to spatial and contextual memory. However, we recently demonstrated that the anterior part of the RSC (aRSC) is required for object recognition (OR) memory consolidation. In this study, we aimed to analyze the requirement of dopaminergic inputs into the aRSC for OR memory consolidation in male rats. We observed amnesia at 24-h long-term memory when we infused SCH23390, a D1/D5 dopamine receptors antagonist, into aRSC immediately after OR training session. However, the same infusion had no effect on OR short-term memory. Then, we analyzed whether the ventral tegmental area (VTA) is necessary for OR consolidation. VTA inactivation by intra-VTA administration of muscimol, a GABAA agonist, immediately after an OR training session induced amnesia when animals were tested at 24 h. Moreover, we observed that this VTA inactivation-induced amnesia was reversed by the simultaneous intra-aRSC delivery of SKF38393, a D1/D5 receptor agonist. Altogether, our results suggest that VTA dopaminergic inputs to aRSC play an important modulatory role in OR memory consolidation.

Participation of Hippocampal 5-HT5A, 5-HT6 and 5-HT7 Serotonin Receptors on the Consolidation of Social Recognition Memory

Social recognition is the ability of animals to identify and recognize a conspecific. The consolidation of social stimuli in long-term memory is crucial for the establishment and maintenance of social groups, reproduction and species survival. Despite its importance, little is known about the circuitry and molecular mechanisms involved in the social recognition memory (SRM). Serotonin (5-hydroxytryptamine, 5-HT) is acknowledged as a major neuromodulator, which plays a key role in learning and memory. Focusing on the more recently described 5-HT receptors, we investigated in the CA1 region of the dorsal hippocampus the participation of 5-HT5A, 5-HT6 and 5-HT7 receptors in the consolidation of SRM. Male Wistar rats cannulated in CA1 were subjected to a social discrimination task. In the sample phase the animals were exposed to a juvenile conspecific for 1 h. Immediately after, they received different pharmacological treatments. Twenty-four hours later, they were submitted to a 5 min retention test in the presence of the previously presented juvenile (familiar) and a novel juvenile. The animals that received infusions of 5-HT5A receptor antagonist SB-699551 (10 µg/µL), 5-HT6 receptor agonist WAY-208466 (0.63 µg/µL) or 5-HT7 receptor agonist AS-19 (5 µg/µL) intra-CA1 were unable to recognize the familiar juvenile. This effect was blocked by the coinfusion of WAY-208466 plus 5-HT6 receptor antagonist SB-271046 (10 µg/µL) or AS-19 plus 5-HT7 receptor antagonist SB-269970 (5 µg/µL). The present study helps to clarify the neurobiological functions of the 5-HT receptors more recently described and extends our knowledge about mechanisms underlying the SRM.

Trans-urocanic acid facilitates spatial memory, implications for Alzheimer's disease

Trans-urocanic acid (trans-UCA) is an isomer of cis-UCA and is widely distributed in the brain, predominantly in the hippocampus and prefrontal cortex. Previous studies have investigated the role of trans-UCA in non-spatial memory; however, its influence on spatial memory remains unclear. In the present study, network pharmacology strategy and behavioral testing were used to evaluate the role of trans-UCA in spatial memory and predict its possible mechanism. The results showed that there are 40 intersecting targets between trans-UCA and spatial memory identified by several databases and Venn diagram, indicating that trans-UCA may be involved in spatial memory. Behavioral results show that trans-UCA facilitates spatial working memory in the Y-maze test as well as spatial recognition memory acquisition, consolidation and retrieval in an object location recognition (OLR) task. Furthermore, PPI (protein-protein interaction) network analysis, GO (gene ontology) and KEGG (Kyoto encyclopedia of genes and genomes) pathway enrichment analyses show that the molecular mechanisms underlying the enhancing effect of trans-UCA on spatial memory are mainly associated with the regulation of insulin, mitogen-activated protein kinase (MAPK) and nuclear factor Kappa B (NF-κB) signaling pathways, serotonergic synapse and arginine and proline metabolism. The results of this study suggest that trans-UCA facilitates spatial memory in the Y-maze test and OLR task and may offer therapeutic potential for Alzheimer's disease (AD). The underlying mechanisms predicted by network pharmacology should be further verified.

Extracellular matrix metalloproteinase-9 (MMP-9) is required in female mice for 17β-estradiol enhancement of hippocampal memory consolidation

Hippocampal plasticity and memory are modulated by the potent estrogen 17β-estradiol (E2). Research on the molecular mechanisms of hippocampal E2 signaling has uncovered multiple intracellular pathways that contribute to these effects, but few have questioned the role that extracellular signaling processes may play in E2 action. Modification of the extracellular matrix (ECM) by proteases like matrix metalloproteinase-9 (MMP-9) is critical for activity-dependent remodeling of synapses, and MMP-9 activity is required for hippocampal learning and memory. Yet little is known about the extent to which E2 regulates MMP-9 in the hippocampus, and the influence this interaction may have on hippocampal memory. Here, we examined the effects of hippocampal MMP-9 activity on E2-induced enhancement of spatial and object recognition memory consolidation. Post-training bilateral infusion of an MMP-9 inhibitor into the dorsal hippocampus of ovariectomized female mice blocked the enhancing effects of E2 on object placement and object recognition memory, supporting a role for MMP-9 in estrogenic regulation of memory consolidation. E2 also rapidly increased the activity of dorsal hippocampal MMP-9 without influencing its protein expression, providing further insight into hippocampal E2/MMP-9 interactions. Together, these results provide the first evidence that E2 regulates MMP-9 to modulate hippocampal memory and highlight the need to further study estrogenic regulation of extracellular modification.

Photostimulation of Ventral Tegmental Area-Insular Cortex Dopaminergic Inputs Enhances the Salience to Consolidate Aversive Taste Recognition Memory via D1-Like Receptors

Taste memory involves storing information through plasticity changes in the neural network of taste, including the insular cortex (IC) and ventral tegmental area (VTA), a critical provider of dopamine. Although a VTA-IC dopaminergic pathway has been demonstrated, its role to consolidate taste recognition memory remains poorly understood. We found that photostimulation of dopaminergic neurons in the VTA or VTA-IC dopaminergic terminals of TH-Cre mice improves the salience to consolidate a subthreshold novel taste stimulus regardless of its hedonic value, without altering their taste palatability. Importantly, the inhibition of the D1-like receptor into the IC impairs the salience to facilitate consolidation of an aversive taste recognition memory. Finally, our results showed that VTA photostimulation improves the salience to consolidate a conditioned taste aversion memory through the D1-like receptor into the IC. It is concluded that the dopamine activity from the VTA into IC is required to increase the salience enabling the consolidation of a taste recognition memory. Notably, the D1-like receptor activity into the IC is required to consolidate both innate and learned aversive taste memories but not appetitive taste memory.

Peripheral Administration of a Cell-Penetrating MOTS-c Analogue Enhances Memory and Attenuates Aβ1-42- or LPS-Induced Memory Impairment through Inhibiting Neuroinflammation.

MOTS-c is a 16-amino acid mitochondrial derivative peptide reported to be involved in regulating insulin and metabolic homeostasis via the AMP activated protein kinase (AMPK). AMPK agonist AICAR has been reported to improve cognition. Previous reports also pointed out that MOTS-c may be effective as a therapeutic option toward the prevention of the aging processes. Therefore, we investigated the roles of MOTS-c in the memory recognition process. The results showed that central MOTS-c not only enhanced object and location recognition memory formation and consolidation but also ameliorated the memory deficit induced by Aβ1-42 or LPS. The memory-ameliorating effects of MOTS-c could be blocked by AMPK inhibitor dorsomorphin. Moreover, MOTS-c treatment significantly increased the phosphorylation of AMPK but not ERK, JNK, and p38 in the hippocampus. The underlying mechanism of MOTS-c neuroprotection may involve inhibiting the activation of astrocytes and microglia and production of proinflammatory cytokines. In addition, we found that peripheral administration of MOTS-c does not cross the blood-brain barrier (BBB) and plays an effect. In order to improve the brain intake of MOTS-c, we screen out (PRR)5, a cell penetrating peptides, as a carrier for MOTS-c into the brain. Then in the NOR task, intranasal or intravenous MP (cell-penetrating MOTS-c analogue) showed good memory performance on memory formation, memory consolidation, and memory impairment. Near-infrared fluorescent experiments showed the real-time biodistribution in brain after intranasal or intravenous infusion of MP. These results suggested that MOTS-c might be a new potential target for treatment of cognitive decline in AD.

Inhibition of PACAP/PAC1/VPAC2 signaling impairs the consolidation of social recognition memory and nitric oxide prevents this deficit

Social recognition memory (SRM) forms the basis of social relationships of animals. It is essential for social interaction and adaptive behavior, reproduction and species survival. Evidence demonstrates that social deficits of psychiatric disorders such as autism and schizophrenia are caused by alterations in SRM processing by the hippocampus and amygdala. Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) and its receptors PAC1, VPAC1 and VPAC2 are highly expressed in these regions. PACAP is a pleiotropic neuropeptide that modulates synaptic function and plasticity and is thought to be involved in social behavior. PACAP signaling also stimulates the nitric oxide (NO) production and targets outcomes to synapses. In the present work, we investigate the effect of the infusion of PACAP-38 (endogenous neuropeptide and potent stimulator of adenylyl cyclase), PACAP 6–38 (PAC1/VPAC2 receptors antagonist) and S-Nitroso-N-acetyl-DL-penicillamine (SNAP, NO donor) in the CA1 region of the hippocampus and in the basolateral amygdala (BLA) on the consolidation of SRM. For this, male Wistar rats with cannulae implanted in CA1 or in BLA were subjected to a social discrimination paradigm, which is based on the natural ability of rodents to investigate unfamiliar conspecifics more than familiar one. In the sample phase (acquisition), animals were exposed to a juvenile conspecific for 1 h. Immediately, 60 or 150 min after, animals received one of different pharmacological treatments. Twenty-four hours later, they were submitted to a 5 min retention test in the presence of the previously presented juvenile (familiar) and a novel juvenile. Animals that received infusions of PACAP 6–38 (40 pg/side) into CA1 immediately after the sample phase or into BLA immediately or 60 min after the sample phase were unable to recognize the familiar juvenile during the retention test. This impairment was abolished by the coinfusion of PACAP 6–38 plus SNAP (5 μg/side). These results show that the blockade of PACAP/PAC1/VPAC2 signaling in the CA1 and BLA during a restricted post-acquisition time window impairs the consolidation of SRM and that the SNAP is able to abolish this deficit. Findings like this could potentially be used in the future to influence studies of psychiatric disorders involving social behavior.

Amphetamine Modulation of Long-Term Object Recognition Memory in Rats: Influence of Stress.

Amphetamine is a potent psychostimulant that increases brain monoamine levels. Extensive evidence demonstrated that norepinephrine is crucially involved in the regulation of memory consolidation for stressful experiences. Here, we investigated amphetamine effects on the consolidation of long-term recognition memory in rats exposed to different intensities of forced swim stress immediately after training. Furthermore, we evaluated whether such effects are dependent on the activation of the peripheral adrenergic system. To this aim, male adult Sprague Dawley rats were subjected to an object recognition task and intraperitoneally administered soon after training with amphetamine (0.5 or 1 mg/kg), or its corresponding vehicle. Rats were thereafter exposed to a mild (1 min, 25 ± 1°C) or strong (5 min, 19 ± 1°C) forced swim stress procedure. Recognition memory retention was assessed 24-h after training. Our findings showed that amphetamine enhances the consolidation of memory in rats subjected to mild stress condition, while it impairs long-term memory performance in rats exposed to strong stress. These dichotomic effects is dependent on stress-induced activation of the peripheral adrenergic response.

Class I HDAC inhibition improves object recognition memory consolidation through BDNF/TrkB pathway in a time-dependent manner

There is increasing evidence showing that HDACs regulates BDNF (brain-derived neurotrophic factor) expression through its interaction with the Bdnf gene promoter, a key regulator to consolidate memory. Although the nuclear mechanisms regulated by HDACs that control BDNF expression have been partially described recently, the temporal events for memory consolidation remain unknown. Hence, in this work, we studied the temporal pattern for the activation of the BDNF/TrkB pathway through class I HDAC inhibition to enhance object recognition memory (ORM) consolidation. To this end, we inhibited class I HDAC into the insular cortex (IC) and a weak ORM protocol was used to assess temporal expression and function of the BDNF/TrkB pathway in the IC. We found that cortical class I HDAC inhibition enhanced long-term ORM, coincident with a clear peak of BDNF expression at 4 h after acquisition. Furthermore, the tyrosine kinase B (TrkB) receptor blockade at 4 h, but not at 8 h, impaired the consolidation of ORM. These results suggest that histone acetylation regulates the temporal expression of BDNF in cortical circuits potentiating the long-term recognition memory.

A novel non‐toxic histone deacetylase inhibitor enhances spatial memory consolidation in male mice

AbstractBackgroundMemory dysfunction is a hallmark of Alzheimer’s disease (AD) and other dementias, yet truly effective treatments for memory loss do not exist. Memory dysfunction stems in part from reduced gene expression that leads to decreased levels of proteins essential for neural plasticity. Gene expression is facilitated by histone acetylation, an epigenetic mechanism that regulates chromatin accessibility. Compounds that maintain histone acetylation, called histone deacetylase inhibitors (HDACi), enhance memory by preventing deacetylation of core histone proteins, which allows for transcriptional machinery to bind open chromatin and increase gene expression. Although HDACi are promising therapeutics that could be used to prevent or delay memory loss associated with AD and other dementias, existing HDACi have poor solubility and undesirable toxicity. To address these shortcomings, our group has developed a novel HDACi compound, MJM‐1, that is brain‐penetrant and shows no evidence of toxicity. Here, we determine the extent to which MJM‐1can enhance memory.MethodsMale C57BL/6 mice were tested in object placement (OP) and object recognition (OR) tasks, which were used to assess spatial and object recognition memory consolidation, respectively. Mice received a post‐training intraperitoneal (i.p.) injection of either negative control (100% DMSO), positive HDACi control (sodium butyrate; 0.6 g/kg NaBu), or one of three doses of MJM‐1(20, 30, or 40 µg/g). During testing, one training object was moved to a new location in the open field (OP task) or was replaced with a novel object (OR task). Mice who remember the training objects should spend more time with the moved and/or novel objects.ResultsMice receiving NaBu, 20 µg/g MJM‐1, or 40 µg/g MJM‐1 spent significantly more time with the moved object, whereas DMSO‐treated controls mice did not, suggesting that the established HDACi NaBu and two doses of the novel HDACi MJM‐1 enhanced spatial memory consolidation. Mice receiving the 30 µg/g dose of MJM‐1 also tended to prefer the moved object. Conversely, none of the doses of MJM‐1 affected object recognition memory.ConclusionThe novel non‐toxic brain penetrant HDACi MJM‐1 can enhance spatial memory consolidation, suggesting encouraging proof of principle for future testing in models of aging and AD.

Molecular Mechanisms in Hippocampus Involved on Object Recognition Memory Consolidation and Reconsolidation

Acquired information is stabilized into long-term memory through a process known as consolidation. Though, after consolidation, when stored information is retrieved they can be again susceptible, allowing modification, updating and strengthening and to be re-stabilized they need a new process referred to as memory reconsolidation. However, the molecular mechanisms of recognition memory consolidation and reconsolidation are not fully understood. Also, considering that the study of the link between synaptic proteins is key to understanding of memory processes, we investigated, in male Wistar rats, molecular mechanisms in the hippocampus involved on object recognition memory (ORM) consolidation and reconsolidation. We verified that the blockade of AMPA receptors (AMPAr) and L-VDCCs calcium channels impaired ORM consolidation and reconsolidation when administered into CA1 immediately after sample phase or reactivation phase and that these impairments were blocked by the administration of AMPAr agonist and of neurotrophin BDNF. Also, the blockade of CaMKII impaired ORM consolidation when administered 3 h after sample phase but had no effect on ORM reconsolidation and its effect was blocked by the administration of BDNF, but not of AMPAr agonist. So, this study provides new evidence of the molecular mechanisms involved on the consolidation and reconsolidation of ORM, demonstrating that AMPAr and L-VDCCs are necessary for the consolidation and reconsolidation of ORM while CaMKII is necessary only for the consolidation and also that there is a link between BDNF and AMPAr, L-VDCCs and CaMKII as well as a link between AMPAr and L-VDCCs on ORM consolidation and reconsolidation.

Suprachiasmatic lesions restore object recognition in down syndrome model mice

The Ts65Dn mouse is a well-studied model of trisomy 21, Down syndrome. This mouse strain has severe learning disability as measured by several rodent learning tests that depend on hippocampal spatial memory function. Hippocampal long-term potentiation (LTP) is deficient in these mice. Short-term daily treatment with low-dose GABA receptor antagonists rescue spatial learning and LTP in Ts65Dn mice leading to the hypothesis that the learning disability is due to GABAergic over-inhibition of hippocampal circuits. The fact that the GABA receptor antagonists were only effective if delivered during the daily light phase suggested that the source of the excess GABA was controlled directly or indirectly by the circadian system. The central circadian pacemaker of mammals is the suprachiasmatic nucleus (SCN), which is largely a GABAergic nucleus. In this study we investigated whether elimination of the SCN in Ts65Dn mice would restore their ability to form recognition memories as tested by the novel object recognition (NOR) task. Full, but not partial lesions of the SCN of Ts65Dn mice normalized their ability to perform on the NOR test. These results suggest that the circadian system modulates neuroplasticity over the time frame involved in the process of consolidation of recognition memories.

Involvement of medial prefrontal cortex NMDA and AMPA/kainate glutamate receptors in social recognition memory consolidation.

Social recognition memory (SRM) enables the distinction between familiar and strange conspecifics, a fundamental ability for sociable species, such as rodents and humans. There is mounting evidence that the medial prefrontal cortex plays a prominent role both in shaping social behavior and in recognition memory. Glutamate is the major excitatory neurotransmitter in the brain, and activity of its ionotropic receptors is known to mediate both synaptic plasticity and consolidation of various types of memories. However, whether these receptors are required in the medial prefrontal cortex (mPFC) for SRM consolidation remains elusive. To address this issue, we submitted rats to a social discrimination paradigm, administered infusions of NMDA- and AMPA/kainate-receptors antagonists into the prelimbic (PrL) subdivision of the mPFC at different post-encoding time points and evaluated long-term memory retention twenty-four hours later. We found that blocking NMDA receptors immediately after the sample phase, but not 3h later, impaired SRM consolidation, whereas the blockade of AMPA/kainate receptors immediately and 3h, but not 6h after the sample phase, prevented long-term memory consolidation. These results highlight the importance of the mPFC in social cognition and may contribute towards the understanding of the dysfunctional social information processing that underlies multiple neuropsychiatric disorders.

Dorsal Hippocampal Actin Polymerization Is Necessary for Activation of G-Protein-Coupled Estrogen Receptor (GPER) to Increase CA1 Dendritic Spine Density and Enhance Memory Consolidation.

Activation of the membrane estrogen receptor G-protein-coupled estrogen receptor (GPER) in ovariectomized mice via the GPER agonist G-1 mimics the beneficial effects of 17β-estradiol (E2) on hippocampal CA1 spine density and memory consolidation, yet the cell-signaling mechanisms mediating these effects remain unclear. The present study examined the role of actin polymerization and c-Jun N-terminal kinase (JNK) phosphorylation in mediating effects of dorsal hippocampally infused G-1 on CA1 dendritic spine density and consolidation of object recognition and spatial memories in ovariectomized mice. We first showed that object learning increased apical CA1 spine density in the dorsal hippocampus (DH) within 40 min. We then found that DH infusion of G-1 increased both CA1 spine density and phosphorylation of the actin polymerization regulator cofilin, suggesting that activation of GPER may increase spine morphogenesis through actin polymerization. As with memory consolidation in our previous work (Kim et al., 2016), effects of G-1 on CA1 spine density and cofilin phosphorylation depended on JNK phosphorylation in the DH. Also consistent with our previous findings, E2-induced cofilin phosphorylation was not dependent on GPER activation. Finally, we found that infusion of the actin polymerization inhibitor, latrunculin A, into the DH prevented G-1 from increasing apical CA1 spine density and enhancing both object recognition and spatial memory consolidation. Collectively, these data demonstrate that GPER-mediated hippocampal spinogenesis and memory consolidation depend on JNK and cofilin signaling, supporting a critical role for actin polymerization in the GPER-induced regulation of hippocampal function in female mice.SIGNIFICANCE STATEMENT Emerging evidence suggests that G-protein-coupled estrogen receptor (GPER) activation mimics effects of 17β-estradiol on hippocampal memory consolidation. Unlike canonical estrogen receptors, GPER activation is associated with reduced cancer cell proliferation; thus, understanding the molecular mechanisms through which GPER regulates hippocampal function may provide new avenues for the development of drugs that provide the cognitive benefits of estrogens without harmful side effects. Here, we demonstrate that GPER increases CA1 dendritic spine density and hippocampal memory consolidation in a manner dependent on actin polymerization and c-Jun N-terminal kinase phosphorylation. These findings provide novel insights into the role of GPER in mediating hippocampal morphology and memory consolidation, and may suggest first steps toward new therapeutics that more safely and effectively reduce memory decline in menopausal women.

Chemogenetic Suppression of Medial Prefrontal-Dorsal Hippocampal Interactions Prevents Estrogenic Enhancement of Memory Consolidation in Female Mice.

The importance of the dorsal hippocampus (DH) in mediating the memory-enhancing effects of the sex-steroid hormone 17β-estradiol (E2) is well established. However, estrogen receptors (ERs) are highly expressed in other brain regions that support memory formation, including the medial prefrontal cortex (mPFC). The mPFC and DH interact to mediate the formation of several types of memory, and behavioral tasks that recruit the mPFC are enhanced by systemic E2 administration, making this region a prime candidate for investigating circuit-level questions regarding the estrogenic regulation of memory. Further, infusion of E2 directly into the DH increases dendritic spine density in both the DH and mPFC, and this effect depends upon rapid activation of cell-signaling pathways in the DH, demonstrating a previously unexplored interaction between the DH and mPFC that led us to question the role of the mPFC in object memory consolidation and the necessity of DH-mPFC interactions in the memory-enhancing effects of E2. Here, we found that infusion of E2 directly into the mPFC of ovariectomized mice increased mPFC apical spine density and facilitated object recognition and spatial memory consolidation, demonstrating that E2 in the mPFC increases spinogenesis and enhances on memory consolidation. Next, chemogenetic suppression of the mPFC blocked the beneficial effects of DH-infused E2 on memory consolidation, indicating that systems-level DH-mPFC interactions are necessary for the memory-enhancing effects of E2. Together, these studies provide evidence that E2 in the mPFC mediates memory formation, and reveal that the DH and mPFC act in concert to support the memory-enhancing effects of E2 in female mice.

Activation of androgen receptors protects intact male mice from memory impairments caused by aromatase inhibition

Although 17β-estradiol (E2) is known to regulate hippocampal function, the specific contributions of hippocampally-synthesized E2 remain unclear. Infusion of the aromatase inhibitor letrozole into the dorsal hippocampus (DH) of ovariectomized mice disrupts object recognition and object placement memory consolidation, suggesting that DH-synthesized E2 is essential for memory. However, the role of DH-synthesized E2 in memory among male rodents is unknown. Here, we examined effects of aromatase inhibition on memory consolidation in male mice. Intact and gonadectomized mice were infused with vehicle or letrozole into the DH immediately post-training in object placement and object recognition tasks. Letrozole blocked memory in both tasks among gonadectomized males only, suggesting that circulating androgens, or a rise in hippocampal androgens due to aromatase inhibition, may support memory consolidation in intact males. To test this hypothesis, intact males were infused with the androgen receptor antagonist flutamide into the DH after object training. A dose-dependent impairment was observed in both tasks, indicating that blocking androgen signaling can impair memory consolidation. To test if hippocampal androgen receptor activation protected intact males from the impairing effects of letrozole, a non-impairing dose of flutamide was co-infused with letrozole. Co-administration of both drugs blocked object placement and object recognition memory consolidation, demonstrating that letrozole impairs memory in intact males only if androgen receptors are blocked. Together, these data suggest that DH-synthesized E2 and androgen receptor activation may work in concert to mediate memory consolidation in intact males, such that androgen receptor activation protects against memory impairments caused by aromatase inhibition.

Chemogenetic inactivation of the dorsal hippocampus and medial prefrontal cortex, individually and concurrently, impairs object recognition and spatial memory consolidation in female mice

The dorsal hippocampus (DH) and medial prefrontal cortex (mPFC) are brain regions essential for processing and storing episodic memory. In rodents, the DH has a well-established role in supporting the consolidation of episodic-like memory in tasks such as object recognition and object placement. However, the role of the mPFC in the consolidation of episodic-like memory tasks remains controversial. Therefore, the present study examined involvement of the DH and mPFC, alone and in combination, in object and spatial recognition memory consolidation in ovariectomized female mice. To this end, we utilized two types of inhibitory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to inactivate the DH alone, the mPFC alone, or both brain regions concurrently immediately after object training to assess the role of each region in the consolidation of object recognition and spatial memories. Our results using single and multiplexed DREADDS suggest that excitatory activity in the DH and mPFC, alone or in combination, is required for the successful consolidation of object recognition and spatial memories. Together, these studies provide critical insight into how the DH and mPFC work in concert to facilitate memory consolidation in female mice.