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Previous studies demonstrate that ethanol dependence induced by repeating cycles of chronic intermittent ethanol vapor exposure (CIE) followed by protracted abstinence produces significant gray matter damage via myelin dysfunction in the rodent medial prefrontal cortex (mPFC) and alterations in neuronal excitability in the mPFC and the dentate gyrus (DG) of the hippocampus. Specifically, abstinence-induced neuroadaptations have been associated with persistent elevated relapse to drinking. The current study evaluated the effects of forced abstinence for 1 day (d), 7 d, 21 d, and 42 d following seven weeks of CIE on synaptic plasticity proteins in the mPFC and DG. Immunoblotting revealed reduced expression of CaMKII in the mPFC and enhanced expression of GABAA and CaMKII in the DG at the 21 d time point, and the expression of the ratio of GluN2A/2B subunits did not change at any of the time points studied. Furthermore, cognitive performance via Pavlovian trace fear conditioning (TFC) was evaluated in 3 d abstinent rats, as this time point is associated with negative affect. In addition, the expression of the ratio of GluN2A/2B subunits and a 3D structural analysis of neurons in the mPFC and DG were evaluated in 3 d abstinent rats. Behavioral analysis revealed faster acquisition of fear responses and reduced retrieval of fear memories in CIE rats compared to controls. TFC produced hyperplasticity of pyramidal neurons in the mPFC under control conditions and this effect was not evident or blunted in abstinent rats. Neurons in the DG were unaltered. TFC enhanced the GluN2A/2B ratio in the mPFC and reduced the ratio in the DG and was not altered by abstinence. These findings indicate that forced abstinence from CIE produces distinct and divergent alterations in plasticity proteins in the mPFC and DG. Fear learning-induced changes in structural plasticity and proteins contributing to it were more profound in the mPFC during forced abstinence. [ABSTRACT FROM AUTHOR]

Abstract A critical feature of episodic memory formation is to associate temporally segregated events as an episode, called temporal association learning. The medial entorhinal cortical-hippocampal (EC-HPC) networks is essential for temporal association learning. We have previously demonstrated that pyramidal cells in the medial EC (MEC) layer III project to the hippocampal CA1 pyramidal cells and are necessary for trace fear conditioning (TFC), which is an associative learning between tone and aversive shock with the temporal gap. On the other hand, Island cells in MECII, project to GABAergic neurons in hippocampal CA1, suppress the MECIII input into the CA1 pyramidal cells through the feed-forward inhibition, and inhibit TFC. However, it remains unknown about how Island cells activity is regulated during TFC. In this study, we report that dopamine D1 receptor is preferentially expressed in Island cells in the MEC. Optogenetic activation of dopamine D1 receptors in Island cells facilitate the Island cell activity and inhibited hippocampal CA1 pyramidal cell activity during TFC. The optogenetic activation caused the impairment of TFC memory recall without affecting contextual fear memory recall. These results suggest that dopamine D1 receptor in Island cells have a crucial role for the regulation of temporal association learning.

A critical feature of episodic memory formation is to associate temporally segregated events as an episode, called temporal association learning. The medial entorhinal cortical-hippocampal (EC-HPC) networks is essential for temporal association learning. We have previously demonstrated that pyramidal cells in the medial EC (MEC) layer III project to the hippocampal CA1 pyramidal cells and are necessary for trace fear conditioning (TFC), which is an associative learning between tone and aversive shock with the temporal gap. On the other hand, Island cells in MECII, project to GABAergic neurons in hippocampal CA1, suppress the MECIII input into the CA1 pyramidal cells through the feed-forward inhibition, and inhibit TFC. However, it remains unknown about how Island cells activity is regulated during TFC. In this study, we report that dopamine D1 receptor is preferentially expressed in Island cells in the MEC. Optogenetic activation of dopamine D1 receptors in Island cells facilitate the Island cell activity and inhibited hippocampal CA1 pyramidal cell activity during TFC. The optogenetic activation caused the impairment of TFC memory recall without affecting contextual fear memory recall. These results suggest that dopamine D1 receptor in Island cells have a crucial role for the regulation of temporal association learning. [ABSTRACT FROM AUTHOR]

Many studies have focused on the role of the medial entorhinal cortex (MEC) in spatial memory and spatial processing. However, more recently, studies have suggested that the functions of the MEC may extend beyond the spatial domain and into the temporal aspects of memory processing. The current study examined the effect of MEC lesions on spatial and nonspatial tasks that require rats to learn and remember information about location or stimulus-stimulus associations across short temporal gaps. MEC- and sham-lesioned male rats were tested on a watermaze delayed match to position (DMP) task and trace fear conditioning (TFC). Rats with MEC lesions were impaired at remembering the platform location after both the shortest (1 min) and the longest (6 h) delays on the DMP task, never performing as precisely as sham rats under the easiest condition and performing poorly at the longest delay. On the TFC task, although MEC-lesioned rats were not impaired at remembering the conditioning context, they showed reduced freezing in response to the previously associated tone. These findings suggest that the MEC plays a role in bridging temporal delays during learning and memory that extend beyond its established role in spatial memory processing.

Previous studies demonstrate that ethanol dependence induced by repeating cycles of chronic intermittent ethanol vapor exposure (CIE) followed by protracted abstinence produces significant gray matter damage via myelin dysfunction in the rodent medial prefrontal cortex (mPFC) and alterations in neuronal excitability in the mPFC and the dentate gyrus (DG) of the hippocampus. Specifically, abstinence-induced neuroadaptations have been associated with persistent elevated relapse to drinking. The current study evaluated the effects of forced abstinence for 1 day (d), 7 d, 21 d, and 42 d following seven weeks of CIE on synaptic plasticity proteins in the mPFC and DG. Immunoblotting revealed reduced expression of CaMKII in the mPFC and enhanced expression of GABAA and CaMKII in the DG at the 21 d time point, and the expression of the ratio of GluN2A/2B subunits did not change at any of the time points studied. Furthermore, cognitive performance via Pavlovian trace fear conditioning (TFC) was evaluated in 3 d abstinent rats, as this time point is associated with negative affect. In addition, the expression of the ratio of GluN2A/2B subunits and a 3D structural analysis of neurons in the mPFC and DG were evaluated in 3 d abstinent rats. Behavioral analysis revealed faster acquisition of fear responses and reduced retrieval of fear memories in CIE rats compared to controls. TFC produced hyperplasticity of pyramidal neurons in the mPFC under control conditions and this effect was not evident or blunted in abstinent rats. Neurons in the DG were unaltered. TFC enhanced the GluN2A/2B ratio in the mPFC and reduced the ratio in the DG and was not altered by abstinence. These findings indicate that forced abstinence from CIE produces distinct and divergent alterations in plasticity proteins in the mPFC and DG. Fear learning-induced changes in structural plasticity and proteins contributing to it were more profound in the mPFC during forced abstinence.

Inducing fear memory extinction by re-presenting a conditioned stimulus (CS) is the foundation of exposure therapy for post-traumatic stress disorder (PTSD). Investigating differences in the ability of different CS presentation patterns to induce extinction learning is crucial for improving this type of therapy. Using a trace fear conditioning paradigm in mice, we demonstrate that spaced presentation of the CS facilitated the extinction of a strong fear memory to a greater extent than continuous CS presentation. These results lay the groundwork for developing more effective exposure therapy techniques for PTSD. • A spaced CS extinguished fear memory similarly for all shock intensities. • A continuous CS extinguished fear memory differently according to shock intensity. • A spaced CS facilitated extinction of a strong fear memory. • A spaced CS extinguished fear memory irrespective of context fear generalization. [ABSTRACT FROM AUTHOR]

Accumulating evidence suggests that the medial prefrontal cortex (mPFC) has been implicated in the acquisition of fear memory during trace fear conditioning in which a conditional stimulus (CS) is paired with an aversive unconditional stimulus (UCS) separated by a temporal gap (trace interval, TI). However, little is known about the role of the prefrontal cortex for short- and long-term trace fear memory formation. Thus, we investigated how the prelimbic (PL) subregion within mPFC in rats contributes to short- and long-term trace fear memory formation using electrolytic lesions and d,l,-2-amino-5-phosphonovaleric acid (APV), an N-methyl-D-aspartate receptor (NMDAR) antagonist infusions into PL. In experiment 1, pre-conditioning lesions of PL impaired freezing to the CS as well as TI during the acquisition and retrieval sessions, indicating that PL is critically involved in trace fear memory formation. In experiment 2, temporary blockade of NMDA receptors in PL impaired the acquisition, but not the expression of short- and long-term trace fear memory. In addition, the inactivation of NMDAR in PL had little effect on locomotor activity, pre-pulse inhibition (PPI), or shock sensitivity. Taken together, these results suggest that NMDA receptor-mediated neurotransmission in PL is required for the acquisition of trace fear memory. [ABSTRACT FROM AUTHOR]

Background The reuniens (Re) and rhomboid (Rh) nuclei (ReRh) of the midline thalamus interconnect the hippocampus and the medial prefrontal cortex. The hippocampus and medial prefrontal cortex are both involved in the acquisition of trace fear conditioning, in which a conditioned stimulus (tone) and an aversive unconditioned stimulus (footshock) are paired but separated in time with a trace interval. Earlier, we demonstrated that ReRh inactivation during trace conditioning impaired the acquisition of cued fear. In contrast, ReRh inactivation during both conditioning and test resulted in heightened fear to tones during retrieval. Because there was a generalized contextual fear on top of heightened fear to tones in the latter experiment, here we aimed to examine the specific importance of the functional ReRh in cued fear and contextual fear through introducing prolonged contextual exposure. Methods The ReRh were pharmacologically inactivated with muscimol (or saline as controls) before each experimental session. Results We showed that although ReRh inactivation before trace fear conditioning impaired the acquisition of cued fear, the animals still acquired a certain level of fear to the tones. However, without the functional ReRh throughout the entire behavioral sessions, these animals showed heightened contextual fear that did not decline much with the passage of time, which generalized to the other context, and fear to tones reoccurred when the tones were presented. Conclusions Our results suggested that functional ReRh are important for proper acquisition and expression of fear to context and tones acquired under trace procedure. [ABSTRACT FROM AUTHOR]

Abstract Fear dysregulation is one of the symptoms found in post-traumatic stress disorder (PTSD) patients. The functional abnormality of the hippocampus is known to be implicated in the development of such pathology. Peroxiredoxin 6 (PRDX6) belongs to the peroxiredoxin family. This antioxidant enzyme is expressed throughout the brain, including the hippocampus. Recent evidence reveals that PRDX6 plays an important role in redox regulation and the modulation of several signaling molecules involved in fear regulation. Thus, we hypothesized that PRDX6 plays a role in the regulation of fear memory. We subjected a systemic Prdx6 knockout (Prdx6 −/− ) mice to trace fear conditioning and observed enhanced fear response after training. Intraventricular injection of lentivirus-carried mouse Prdx6 into the 3rd ventricle reduced the enhanced fear response in these knockout mice. Proteomic analysis followed by validation of western blot analysis revealed that several proteins in the MAPK pathway, such as NTRK2, AKT, and phospho-ERK1/2, cPLA2 were significantly upregulated in the hippocampus of Prdx6 −/− mice during the retrieval stage of contextual fear memory. The distribution of PRDX6 found in the astrocytes was also observed throughout the hippocampus. This study identifies PRDX6 as a participant in the regulation of fear response. It suggests that PRDX6 and related molecules may have important implications for understanding fear-dysregulation associated disorders like PTSD.

In humans and rodents, the entorhinal cortical (EC)‐hippocampal (HPC) circuit is crucial for the formation and recall of memory, preserving both spatial information and temporal information about the occurrence of past events. Both modeling and experimental studies have revealed circuits within this network that play crucial roles in encoding space and context. However, our understanding about the time‐related aspects of memory is just beginning to be understood. In this review, we first describe updates regarding recent anatomical discoveries for the EC‐HPC network, as several important neural circuits critical for memory formation have been discovered by newly developed neural tracing technologies. Second, we examine the complementary roles of multiple medial entorhinal cortical inputs, including newly discovered circuits, into the hippocampus for the temporal and spatial aspects of memory. Finally, we will discuss how temporal and contextual memory information is integrated in HPC cornu ammonis 1 cells. We provide new insights into the neural circuit mechanisms for anatomical and functional segregation and integration of the temporal and spatial aspects of memory encoding in the EC‐HPC networks. [ABSTRACT FROM AUTHOR]

Aging is marked by an accumulation of damaged and modified brain proteins, and the ubiquitin-proteasome system (UPS) is important for cellular protein degradation. Recent work has established a critical role for the UPS in memory and synaptic plasticity, but the role of the UPS in age-related cognitive decline remains poorly understood. We trained young, middle-aged, and aged male and female rats using trace fear conditioning (TFC) to investigate the effects of age and sex on memory. We then measured markers of UPS-related protein degradation (phosphorylation of the Rpt6 proteasome regulatory subunit and K48-linked polyubiquitination) using western blots. We found that aged males, but not aged females, showed behavioral deficits at memory retrieval. Aged males also displayed reduced phosphorylation of the Rpt6 proteasome subunit and accumulation of K48 in the basolateral amygdala, while aged females displayed a similar pattern in the medial prefrontal cortex. These findings suggest that markers of UPS function are differentially affected by age and sex in a brain region-dependent manner. Together these results provide an important step toward understanding the UPS and circuit-level differences in aging males and females.

Aging is marked by an accumulation of damaged and modified brain proteins, and the ubiquitin-proteasome system (UPS) is important for cellular protein degradation. Recent work has established a critical role for the UPS in memory and synaptic plasticity, but the role of the UPS in age-related cognitive decline remains poorly understood. We trained young, middle-aged, and aged male and female rats using trace fear conditioning (TFC) to investigate the effects of age and sex on memory. We then measured markers of UPS-related protein degradation (phosphorylation of the Rpt6 proteasome regulatory subunit and K48-linked polyubiquitination) using western blots. We found that aged males, but not aged females, showed behavioral deficits at memory retrieval. Aged males also displayed reduced phosphorylation of the Rpt6 proteasome subunit and accumulation of K48 in the basolateral amygdala, while aged females displayed a similar pattern in the medial prefrontal cortex. These findings suggest that markers of UPS function are differentially affected by age and sex in a brain region-dependent manner. Together these results provide an important step toward understanding the UPS and circuit-level differences in aging males and females. [ABSTRACT FROM AUTHOR]

Accumulating evidence suggests that the medial prefrontal cortex (mPFC) has been implicated in the acquisition of fear memory during trace fear conditioning in which a conditional stimulus (CS) is paired with an aversive unconditional stimulus (UCS) separated by a temporal gap (trace interval, TI). However, little is known about the role of the prefrontal cortex for short- and long-term trace fear memory formation. Thus, we investigated how the prelimbic (PL) subregion within mPFC in rats contributes to short- and long-term trace fear memory formation using electrolytic lesions and d,l,-2-amino-5-phosphonovaleric acid (APV), an N-methyl-D-aspartate receptor (NMDAR) antagonist infusions into PL. In experiment 1, pre-conditioning lesions of PL impaired freezing to the CS as well as TI during the acquisition and retrieval sessions, indicating that PL is critically involved in trace fear memory formation. In experiment 2, temporary blockade of NMDA receptors in PL impaired the acquisition, but not the expression of short- and long-term trace fear memory. In addition, the inactivation of NMDAR in PL had little effect on locomotor activity, pre-pulse inhibition (PPI), or shock sensitivity. Taken together, these results suggest that NMDA receptor-mediated neurotransmission in PL is required for the acquisition of trace fear memory.

Fear dysregulation is one of the symptoms found in post-traumatic stress disorder (PTSD) patients. The functional abnormality of the hippocampus is known to be implicated in the development of such pathology. Peroxiredoxin 6 (PRDX6) belongs to the peroxiredoxin family. This antioxidant enzyme is expressed throughout the brain, including the hippocampus. Recent evidence reveals that PRDX6 plays an important role in redox regulation and the modulation of several signaling molecules involved in fear regulation. Thus, we hypothesized that PRDX6 plays a role in the regulation of fear memory. We subjected a systemic Prdx6 knockout (Prdx6−/−) mice to trace fear conditioning and observed enhanced fear response after training. Intraventricular injection of lentivirus-carried mouse Prdx6 into the 3rd ventricle reduced the enhanced fear response in these knockout mice. Proteomic analysis followed by validation of western blot analysis revealed that several proteins in the MAPK pathway, such as NTRK2, AKT, and phospho-ERK1/2, cPLA2 were significantly upregulated in the hippocampus of Prdx6−/− mice during the retrieval stage of contextual fear memory. The distribution of PRDX6 found in the astrocytes was also observed throughout the hippocampus. This study identifies PRDX6 as a participant in the regulation of fear response. It suggests that PRDX6 and related molecules may have important implications for understanding fear-dysregulation associated disorders like PTSD. [ABSTRACT FROM AUTHOR]

Abstract Introduction Cognitive deficits during aging are pervasive across species and learning paradigms. One of the major mechanisms thought to play a role in age‐related memory decline is dysregulated calcium (Ca2+) homeostasis. Aging is associated with impaired function of several calcium‐regulatory mechanisms, including calcium‐binding proteins that normally support intracellular Ca2+ regulation. This age‐related calcium‐binding protein dysfunction and changes in expression lead to disrupted maintenance of intracellular Ca2+, thus contributing to memory decline. Other work has found that age‐related cognitive deficits can be mitigated by either blocking Ca2+ entry into the cytosol or preventing its release from intracellular Ca2+ stores. However, the effect of calcium‐binding protein administration on cognitive function during aging is not well‐understood. Our laboratory has previously shown that the calcium‐binding protein apoaequorin (AQ) is neuroprotective during oxygen–glucose deprivation, a model of in vitro ischemia characterized by calcium‐induced excitotoxicity. The current experiments assessed the effect of direct dorsal hippocampal AQ infusion on trace and context fear memory in adult and aged rats. Methods Adult (3–6 months) and aged (22–26 months) male F344 rats were randomly assigned to different experimental infusion groups before undergoing trace fear conditioning and testing. In experiment 1, rats received bilateral dorsal hippocampal infusions of either vehicle or AQ (4% w/v) 24 hr before trace fear conditioning. In experiment 2, rats received bilateral dorsal hippocampal infusions of either vehicle or 4% AQ 1 hr before trace fear conditioning and 1 hr before testing. Results Aged rats displayed impaired trace and context fear memory. While a single AQ infusion 24 hr before trace fear conditioning was insufficient to rescue age‐related trace fear memory deficits, AQ infusion 1 hr before both conditioning and testing abolished age‐related context fear memory deficits. Conclusions These results suggest that intrahippocampal infusion of AQ may reverse aging‐related deficits in hippocampus‐dependent context fear memory.

Introduction: Cognitive deficits during aging are pervasive across species and learning paradigms. One of the major mechanisms thought to play a role in age‐related memory decline is dysregulated calcium (Ca2+) homeostasis. Aging is associated with impaired function of several calcium‐regulatory mechanisms, including calcium‐binding proteins that normally support intracellular Ca2+ regulation. This age‐related calcium‐binding protein dysfunction and changes in expression lead to disrupted maintenance of intracellular Ca2+, thus contributing to memory decline. Other work has found that age‐related cognitive deficits can be mitigated by either blocking Ca2+ entry into the cytosol or preventing its release from intracellular Ca2+ stores. However, the effect of calcium‐binding protein administration on cognitive function during aging is not well‐understood. Our laboratory has previously shown that the calcium‐binding protein apoaequorin (AQ) is neuroprotective during oxygen–glucose deprivation, a model of in vitro ischemia characterized by calcium‐induced excitotoxicity. The current experiments assessed the effect of direct dorsal hippocampal AQ infusion on trace and context fear memory in adult and aged rats. Methods: Adult (3–6 months) and aged (22–26 months) male F344 rats were randomly assigned to different experimental infusion groups before undergoing trace fear conditioning and testing. In experiment 1, rats received bilateral dorsal hippocampal infusions of either vehicle or AQ (4% w/v) 24 hr before trace fear conditioning. In experiment 2, rats received bilateral dorsal hippocampal infusions of either vehicle or 4% AQ 1 hr before trace fear conditioning and 1 hr before testing. Results: Aged rats displayed impaired trace and context fear memory. While a single AQ infusion 24 hr before trace fear conditioning was insufficient to rescue age‐related trace fear memory deficits, AQ infusion 1 hr before both conditioning and testing abolished age‐related context fear memory deficits. Conclusions: These results suggest that intrahippocampal infusion of AQ may reverse aging‐related deficits in hippocampus‐dependent context fear memory. [ABSTRACT FROM AUTHOR]

Brain aging is accompanied by an accumulation of damaged proteins, which results from deterioration of cellular quality control mechanisms and decreased protein degradation. The ubiquitin-proteasome system (UPS) is the primary proteolytic mechanism responsible for targeted degradation. Recent work has established a critical role of the UPS in memory and synaptic plasticity, but the role of the UPS in age-related cognitive decline remains poorly understood. Here, we measured markers of UPS function and related them to fear memory in rats. Our results show that age-related memory deficits are associated with reductions in phosphorylation of the Rpt6 proteasome regulatory subunit and corresponding increases in lysine-48 (K48)-linked ubiquitin tagging within the basolateral amygdala. Increases in K48 polyubiquitination were also observed in the medial prefrontal cortex and dorsal hippocampus. These data suggest that protein degradation is a critical component of age-related memory deficits. This extends our understanding of the relationship between the UPS, aging, and memory, which is an important step toward the prevention and treatment of deficits associated with normal cognitive aging and memory-related neurodegenerative diseases. • Older rats show clear memory impairment when tested with trace fear conditioning. • In aged animals, the activity-driven enhancement of ubiquitin-proteasome system mediated protein degradation normally seen during memory retrieval was significantly attenuated in some brain areas. • The degree of behavioral impairment in middle aged and old rats was related to the degree of ubiquitin-proteasome system dysfunction in the basolateral amygdala. [ABSTRACT FROM AUTHOR]

• Arc protein – a neuroplasticity marker – is expressed across hippocampal subfields. • Trace fear conditioning uniquely enhances Arc protein across hippocampal subfields. • Dorsal CA3 subfield may play a unique role in representing the context. • Ventral CA3 Arc protein may reflect CS processing. • Critical engagement of CA3 may be modulated by learning a CS-noUS association. Arc (Activity-regulated cytoskeleton-associated protein) is an effector neuronal immediate-early gene (IEG) and has been closely linked to behaviorally-induced neuronal plasticity. The present studies examined the regionally-selective, dissociable patterns of Arc expression induced by Pavlovian trace fear conditioning, delay fear conditioning, and contextual fear conditioning as well as novel context exposure. This research was guided by anatomical studies identifying heterogeneity of connectivity across the transverse (CA1, CA3) and septo-temporal (dorsal vs. ventral) axes of the hippocampus; companion neuropsychological experiments suggest that these subregions likely play functionally dissociable roles in different forms of hippocampal-dependent learning. Hence the primary goal of the present study was to characterize the expression of Arc protein across both the septotemporal and transverse axes of the hippocampus induced by hippocampal dependent trace fear conditioning and compare these expression patterns to those induced by other fear conditioning paradigms. A second goal of these studies was to explore which specific paradigmatic features of the fear conditioning task itself are responsible for the observed patterns of Arc expression. The results of these studies suggest that, within the dorsal hippocampus, Arc expression in CA3 induced by trace fear conditioning may play a unique role in representing the context, while Arc protein expression within ventral CA3 may reflect CS processing. Arc protein expression in dorsal and ventral CA1 are likely not meaningfully involved in trace fear conditioning as there is either a lack of significant enhancement (dorsal CA1) or enhancement is not unique to subjects trained in trace fear conditioning (ventral CA1). The specific regional pattern of Arc protein enhancement induced by trace fear conditioning may reflect the unique temporal parameters of the task which critically engages the hippocampus in processing both contextual representations as well as the explicit CS. This additional hippocampal processing may account for the greater enhancement in Arc protein in dorsal and ventral CA3 for subjects trained in trace fear conditioning compared to novel context exposure, or contextual and delay fear conditioning. [ABSTRACT FROM AUTHOR]

• Prelimbic muscarinic signaling is required for trace and contextual fear memories. • The estrous cycle gates the fear memory-impairing effects of scopolamine in females. • A higher dose of scopolamine is required to impair fear memory in females than males. • Scopolamine suppresses subsequent drug-free acquisition to the originally trained cue. The association of a sensory cue and an aversive footshock that are separated in time, as in trace fear conditioning, requires persistent activity in prelimbic cortex during the cue-shock interval. The activation of muscarinic acetylcholine receptors has been shown to facilitate persistent firing of cortical cells in response to brief stimulation, and muscarinic antagonists in the prefrontal cortex impair working memory. It is unknown, however, if the acquisition of associative trace fear conditioning is dependent on muscarinic signaling in the prefrontal cortex. Here, we delivered the muscarinic receptor antagonist scopolamine to the prelimbic cortex of rats prior to trace fear conditioning and tested their memories of the cue and training context the following day. The effect of scopolamine on working memory performance was also tested using a spatial delayed non-match to sample task. Male and female subjects were included to examine potential sex differences in the modulation of memory formation, as we have previously observed for pituitary adenylate cyclase-activating polypeptide signaling in the prefrontal cortex (Kirry et al., 2018). We found that pre-training administration of intra-prelimbic scopolamine impaired the formation of cued and contextual fear memories in males, but not females at a dose that impairs spatial working memory in both sexes. Fear memory formation in females was impaired by a higher dose of scopolamine and this impairment was gated by estrous cycle stage: scopolamine failed to impair memory in rats in the diestrus or proestrus stages of the estrous cycle. These findings add to the growing body of evidence that the prefrontal cortex is sexually dimorphic in learning and memory and additionally suggest that males and females differentially engage prefrontal neuromodulatory systems in support of learning. [ABSTRACT FROM AUTHOR]

Abstract Adult male and female GFAP-TK transgenic rats experienced six weeks of chronic intermittent ethanol vapor inhalation (CIE). During the last week of CIE, a subset of male and female TK rats were fed with Valcyte to ablate neural progenitor cells (NPCs). Seventy-two hours after CIE cessation, all CIE and age-matched ethanol naïve controls experienced auditory trace fear conditioning (TFC). Twenty-four hours later all animals were tested for cue-mediated retrieval in the fear context. Adult male CIE rats showed a significant burst in NPCs paralleled by reduction in fear retrieval compared to naïve controls and Valcyte treated CIE rats. Adult female CIE rats did not show a burst in NPCs and showed similar fear retrieval compared to naïve controls and Valcyte treated CIE rats, indicating that CIE-mediated impairment in fear memory and its regulation by NPCs was sex dependent. Valcyte significantly reduced Ki-67 and NeuroD labeled cells in the dentate gyrus (DG) in both sexes, demonstrating a role for NPCs in reduced fear retrieval in males. Valcyte prevented adaptations in GluN2A receptor expression and synaptoporin density in the DG in males, indicating that NPCs contributed to alterations in plasticity-related proteins and mossy fiber projections that were associated with reduced fear retrieval. These data suggest that DG NPCs born during withdrawal and early abstinence from CIE are aberrant, and could play a role in weakening long-term memory consolidation dependent on the hippocampus. Highlights • Withdrawal from chronic ethanol increases neural progenitor cells in the dentate gyrus in male rats. • Increase in neural progenitor cells is mechanistically linked to chronic ethanol-induced amnesic effects. • Aberrant burst in neural progenitor cells regulates plasticity related proteins in the dentate gyrus. [ABSTRACT FROM AUTHOR]

Impairments in behavior and cognition are common in individuals diagnosed with fetal alcohol spectrum disorders (FASD). In this study, FASD model rats were intragastrically intubated with ethanol (5 g/kg/day; 5E), sham-intubated (SI), or maintained as naïve controls (NC) over postnatal days (PD) 4–9. Ethanol exposure during this human third trimester-equivalent period induces persistent impairments in hippocampus-dependent learning and memory. The ability of ibuprofen (IBU), a non-steroidal anti-inflammatory drug, to diminish ethanol-induced neuroinflammation and rescue deficits in hippocampus-dependent trace fear conditioning (TFC) was investigated in 5E rats. Phosphate buffered saline vehicle (VEH) or IBU was injected 2 h following ethanol exposure over PD4-9, followed by quantification of inflammation-related genes in the dorsal hippocampus of PD10 rats. The 5E-VEH rats exhibited significant increases in Il1b and Tnf , but not Itgam or Gfap , relative to NC, SI-VEH, and 5E-IBU rats. In separate groups of PD31-33 rats, conditioned fear (freezing) was significantly reduced in 5E-VEH rats during TFC testing, but not acquisition, compared to SI-VEH and, critically, 5E-IBU rats. Results suggest neuroimmune activation in response to ethanol within the neonate hippocampus contributes to later-life cognitive dysfunction. [ABSTRACT FROM AUTHOR]

Repeated exposure to high levels of stress hormones can enhance contextual and discrete fear conditioning in rats. A common belief is that this enhanced fear memory is largely mediated by the amygdala because both contextual and discrete fear conditioning are dependent on an intact amygdala. However, trace fear conditioning is thought to be amygdala independent, and therefore, it is not clear what impact stress would have on this form of fear learning. Here, we examined whether the stress hormone corticosterone (CORT) would enhance memory in a hippocampal-dependent trace fear conditioning test. Male Long-Evans rats received either 40 mg/kg of CORT or vehicle injections for 21 consecutive days. On day 22, rats received either 1, 2, or 5 tone-trace-shock pairings. On day 23, the rats were tested for behavior to the conditioned tone cues in a novel context. We found that CORT significantly increased the acquisition of trace conditioned fear. We also found that CORT significantly increased recall of trace conditioned cues, but only when a 2 trace-pairing protocol was used during training. These results suggest that CORT can enhance non-amygdala forms of fear learning and memory and that high levels of stress hormones modify the physiological substrates that mediate emotionally driven behavior in tasks that are less dependent on amygdala functioning. [ABSTRACT FROM AUTHOR]

Temporal associative learning binds discontiguous conditional stimuli (CSs) and unconditional stimuli (USs), possibly by maintaining CS information in the hippocampus after its offset. Yet, how learning regulates such maintenance of CS information in hippocampal circuits remains largely unclear. Using the auditory trace fear conditioning (TFC) paradigm, we identify a projection from the CA1 to the subiculum critical for TFC. Deep-brain calcium imaging shows that the peak of trace activity in the CA1 and subiculum is extended toward the US and that the CS representation during the trace period is enhanced during learning. Interestingly, such plasticity is consolidated only in the CA1, not the subiculum, after training. Moreover, CA1 neurons, but not subiculum neurons, increasingly become active during CS-and-trace and shock periods, respectively, and correlate with CS-evoked fear retrieval afterward. These results indicate that learning dynamically enhances stimulus information maintenance in the CA1-subiculum circuit during learning while storing CS and US memories primarily in the CA1 area. [Display omitted] • Both CA1 and subiculum maintain stimulus information in the post-stimulus trace periods • The CA1-to-subiculum projection is critical for temporal associative learning • Continuous learning promotes a better and longer maintenance of stimulus information • Learning-induced plasticity is primarily consolidated in CA1 but not subiculum Using miniscope Ca2+ imaging and optogenetics in behaving mice, Bai et al. demonstrate a learning-induced plasticity of stimulus information maintenance in the CA1 and subiculum. Such plasticity results in enhanced and prolonged maintenance of stimulus information and is critical for the formation of temporal associative memory. [ABSTRACT FROM AUTHOR]

Exposure to lead (Pb) remains a significant public health concern. Lead exposure in early life impairs the normal development of numerous cognitive and neurobehavioral processes. Previous work has shown that the effects of developmental Pb exposure on gene expression patterns in the brain are modulated by various factors including the developmental timing of the exposure, level of exposure, sex, and genetic background. Using gene microarray profiling, we previously reported a significant strain-specific effect of Pb exposure on the hippocampal transcriptome, with the greatest number of differentially expressed transcripts in Long Evans (LE) rats and the fewest in Sprague Dawley (SD) rats. The present study examined the extent to which this differential effect of Pb on hippocampal gene expression might influence behavior. Animals (males and females) were tested in a trace fear conditioning paradigm to evaluate effects of Pb exposures (perinatal (PERI; gestation to postnatal day 21) or early postnatal (EPN; postnatal day 1 to day 21)) on associative learning and memory. All animals (Pb-exposed and non-Pb-exposed controls) showed normal acquisition of the conditioned stimulus (tone)-unconditioned stimulus (footshock) association. Long Evans rats showed a significant deficit in short- and long-term recall, influenced by sex and the timing of Pb exposure (PERI or EPN). In contrast, Pb exposure had no significant effect on memory consolidation or recall in any SD rats. These results further demonstrate the important influence of genetic background to the functional outcomes from developmental Pb exposure. [ABSTRACT FROM AUTHOR]

The Coffin–Lowry syndrome (CLS) is a syndromic form of intellectual disability caused by loss-of-function of the RSK2 serine/threonine kinase encoded by the rsk2 gene. Rsk2 knockout mice, a murine model of CLS, exhibit spatial learning and memory impairments, yet the underlying neural mechanisms are unknown. In the current study, we examined the performance of Rsk2 knockout mice in cued, trace and contextual fear memory paradigms and identified selective deficits in the consolidation and reconsolidation of hippocampal-dependent fear memories as task difficulty and hippocampal demand increase. Electrophysiological, biochemical and electron microscopy analyses were carried out in the dentate gyrus of the hippocampus to explore potential alterations in neuronal functions and structure. In vivo and in vitro electrophysiology revealed impaired synaptic transmission, decreased network excitability and reduced AMPA and NMDA conductance in Rsk2 knockout mice. In the absence of RSK2, standard measures of short-term and long-term potentiation (LTP) were normal, however LTP-induced CREB phosphorylation and expression of the transcription factors EGR1/ZIF268 were reduced and that of the scaffolding protein SHANK3 was blocked, indicating impaired activity-dependent gene regulation. At the structural level, the density of perforated and non-perforated synapses and of multiple spine boutons was not altered, however, a clear enlargement of spine neck width and post-synaptic densities indicates altered synapse ultrastructure. These findings show that RSK2 loss-of-function is associated in the dentate gyrus with multi-level alterations that encompass modifications of glutamate receptor channel properties, synaptic transmission, plasticity-associated gene expression and spine morphology, providing novel insights into the mechanisms contributing to cognitive impairments in CLS.

The nucleus reuniens (RE) and the perirhinal cortex (PRC) are two major relay stations that interconnect the hippocampus (HPC) and the medial prefrontal cortex (mPFC). Previous studies have shown that both the RE and the PRC are involved in the acquisition of trace fear conditioning. However, the respective contribution of the two regions is unclear. In this study, we used pharmacological approach to compare their roles. Our data suggested that inactivation of the RE or the PRC during conditioning partially impaired, whereas inactivation of both areas totally abolished, the encoding of trace fear. We next examined whether the impaired encoding of trace fear under RE inactivation can be rescued with enhanced cholinergic tone in the PRC, and vice versa. Against our hypothesis, regardless of whether the RE was on-line or not, animals failed to encode trace fear when further engaging cholinergic activities in the PRC. Conversely, depending on PRC activation level during conditioning, further recruiting cholinergic activities in the RE led to a down-shift of fear response during retrieval. Our results revealed that the RE and the PRC were necessary for the encoding of trace fear. Moreover, there was differential importance of cholinergic modulation during the process., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Mechanisms underlying delay fear conditioning in which conditioned stimuli (CS) are paired and co-terminated with unconditioned stimuli (US), have been extensively characterized, thus expanding knowledge concerning learning and memory. However, trace fear conditioning in which CS and US are separated by trace interval periods, has received much less attention though it involves cognitive processes including timing and working memories. Various brain regions including the hippocampus are known to play an important role in memory acquisition and/or retrieval of trace fear conditioning. However, neural correlates, which are specific for the discrete steps in trace fear conditioning, have not been characterized thoroughly. Here, we investigated the network activities between the dorsal and ventral hippocampi at different stages of memory processing after trace fear conditioning. When fear memory was retrieved successfully, theta synchronization between the two regions was enhanced relative to preconditioning levels. The enhancement in theta synchronization was observed only during the trace interval period but not during CS presentation or after the trace interval period. Thus, the enhanced theta synchronization between the dorsal and ventral hippocampi may underlie a cognitive process associated with the trace interval period when fear memory is retrieved successfully. [ABSTRACT FROM AUTHOR]

Rationale: Levels of kynurenic acid (KYNA), an endogenous negative modulator of alpha 7 nicotinic acetylcholine receptors (α7nAChRs) and antagonist at glutamatergic N-methyl- d-aspartate receptors (NMDARs), are elevated in the brain of patients with schizophrenia (SZ). In rats, dietary exposure to KYNA's immediate precursor kynurenine during the last week of gestation produces neurochemical and cognitive deficits in adulthood that resemble those seen in patients with SZ. Objectives: The present experiments examined whether prenatal kynurenine exposure results in age-dependent changes in the kynurenine pathway (KP), expression of selected receptors, and cognitive function. Methods: Pregnant dams were fed unadulterated mash (progeny = ECON) or mash containing kynurenine (100 mg/day; progeny = EKYN) from embryonic day (ED) 15 to 22. Male offspring were assessed as juveniles, i.e., prior to puberty (postnatal day [PD] 32), or as adults (PD70) for brain KYNA levels, α7nAChR and NMDAR gene expression, and performance on a trace fear conditioning (TFC) task. Results: KYNA levels were comparable between juvenile ECON and EKYN rats, whereas EKYN adults exhibited a ~3-fold increase in brain KYNA relative to ECONs. NR2A expression was persistently reduced (30-40 %) in EKYN rats at both ages. Compared to ECON adults, there was a 50 % reduction in NR1, and a trend toward decreased α7nAChR expression, in adult EKYN rats. Surprisingly, juvenile EKYN rats performed significantly better in the TFC paradigm than controls, whereas adult EKYN animals showed the predicted deficits. Conclusions: Collectively, our results provide evidence that KP changes in the fetal brain alter neuronal development and cause age-dependent effects on neurochemistry and cognitive performance. [ABSTRACT FROM AUTHOR]

Background Ethanol (EtOH) exposure in neonate rats during a period comparable to the human third trimester, postnatal days ( PD) 4 to 9, leads to persistent deficits in forebrain-dependent cognitive function-modeling the dysfunction seen in individuals diagnosed with fetal alcohol spectrum disorders. EtOH-exposed adult rats are impaired in auditory trace fear conditioning ( TFC), a form of Pavlovian conditioning in which a neutral conditioned stimulus ( CS; tone) is followed by an aversive unconditioned stimulus ( US; footshock), with both stimuli separated in time by a stimulus-free 'trace' interval ( TI). TFC acquisition depends on N-methyl- d-aspartate NMDA receptor ( NMDAR) activation in the dorsal hippocampus ( DH), ventral hippocampus ( VH), and medial prefrontal cortex ( mPFC). Methods Male and female rat pups were sham-intubated ( SI) or intragastrically intubated with EtOH (5E; 5 g/kg/d) over PD 4 to 9 and, as adults, submitted to TFC with a 15-second tone CS and 30-second TI. Whole-cell tissue lysates from the DH, VH, and mPFC of TFC rats and DH synaptic/extrasynaptic membrane fractions from experimentally naïve animals were analyzed via Western blot for NMDAR subunit (GluN1, GluN2A, GluN2B) expression. Results Freezing behavior during CS-alone test trials was significantly reduced in both male and female 5E rats, relative to same-sex controls. Western blot results based on DH tissue samples revealed a greater proportion of GluN2A to GluN2B subunits in 5E rats, relative to SI rats, and significantly reduced synaptic GluN2B and PSD-95 expression. Conclusions EtOH-induced changes in DH NMDAR subunit expression-particularly synaptic GluN2B, which is critical for TFC-are proposed to weaken long-term memory consolidation and, during behavioral testing, diminish CS-evoked freezing behavior. [ABSTRACT FROM AUTHOR]

Accumulating evidence suggests that the lateral nucleus of the amygdala (LA) stores associative memory in the form of enhanced neural response to the sensory input following classical fear conditioning in which the conditioned stimulus (CS) and the unconditioned stimulus (US) are presented in a temporally continuous manner. However, little is known about the role of the LA in trace fear conditioning where the CS and the US are separated by a temporal gap. Single-unit recordings of LA neurons before and after trace fear conditioning revealed that the short-latency activity to the CS offset, but not that to the onset, increased significantly and accompanied the conditioned fear response. The increased short-latency activity was evident in two aspects: the number of offset-responsive neurons was increased and the latency of the neuronal response to the CS offset was shortened. On the contrary, changes in the firing rate to either the onset or the offset were negligible following unpaired presentations of the CS and US. In sum, our results suggest that increased synaptic efficacy in the CS offset pathway in the LA might underlie the association between temporally distant stimuli in trace fear conditioning. [ABSTRACT FROM AUTHOR]

Highlights: [•] We test how the neural circuit for trace fear extinction differs from that of delay. [•] Glutamate receptor blockade in the amygdala impairs delay but not trace extinction [•] pERK is increased in the RSC and not the amygdala for trace extinction. [•] Intra-RSC blockade of NMDA receptors impairs trace but not delay extinction. [•] The RSC, instead of the amygdala, is required for complex trace fear extinction. [Copyright &y& Elsevier]

Utilizing a rat model of fetal alcohol spectrum disorder (FASD). ethanol was administered over postnatal days (PD) 4 to 9. As adults, control and ethanol rats underwent trace fear conditioning (TFC), in which a tone conditioned stimulus (CS) and footshock unconditioned stimulus (US) were repeatedly paired, though the two stimuli never overlapped in time. Following training in Experiment 1, conditioned fear (freezing) to the tone CS was dose-dependently reduced in ethanol rats relative to controls. Experiment 2 was designed to test whether the TFC deficit varied based on the duration of the trace interval (TI; time from CS offset to US onset). Holding the time separating CS onset from US onset constant at 20 sec, control and ethanol rats were trained with a 5 or 15 sec tone CS. followed 15 or 5 sec later, respectively, by the US. Conditioned fear to the tone CS was significantly reduced in high dose ethanol rats trained with the 15 sec TI only. Acquisition and consolidation of trace fear memories relies on forebrain /V-methyl-D-aspartate receptor (NMDAR) signaling, including the downstream phosphorylation of ex-tracellular signal-regulated kinasel/2 (pERKl/2). Separate rats were trained with the 5 or 15 sec TI and then sacrificed 1 hr later. Significant reductions in pERKl/2-positive neurons were seen in areas CAI and CA3 of the dorsal hippocampus (DH) following training at both Tis in ethanol rats. The disruption of DH learning-dependent plasticity appears tied to freezing behavior in ethanol rats, but only when the training stimuli are separated by more than 5 sec. [ABSTRACT FROM AUTHOR]

• Ventral hippocampal neurons in both sexes robustly encode the shock UCS. • Ventral hippocampal neurons show only modest encoding of the CS and no encoding of the trace interval. • Ventral hippocampal shock-evoked activity modulates the expression of learned fear at test in a sex-specific manner. The hippocampus is crucial for associative fear learning when the anticipation of threat requires temporal or contextual binding of predictive stimuli as in trace and contextual fear conditioning. Compared with the dorsal hippocampus, far less is known about the contribution of the ventral hippocampus to fear learning. The ventral hippocampus, which is highly interconnected with defensive and emotional networks, has a prominent role in both innate and learned affective behaviors including anxiety, fear, and reward. Lesions or temporary inactivation of the ventral hippocampus impair both cued and contextual fear learning, but whether the ventral hippocampal role in learning is driven by affective processing, associative encoding, or both is not clear. Here, we used trace fear conditioning in mixed sex cohorts to assess the contribution of shock-encoding to the acquisition of cued and contextual fear memories. Trace conditioning requires subjects to associate an auditory conditional stimulus (CS) with a shock unconditional stimulus (UCS) that are separated in time by a 20-s trace interval. We first recorded neuronal activity in the ventral hippocampus during trace fear conditioning and found that ventral CA1 predominantly encoded the shock reinforcer. Potentiated firing to the CS was evident at testing, but no encoding of the trace interval was observed. We then tested the necessity of shock encoding for conditional fear acquisition by optogenetically silencing ventral hippocampal activity during the UCS on each trial of training. Contrary to our predictions, preventing hippocampal shock-evoked firing did not impair associative fear. Instead, it led to a more prolonged expression of CS freezing across test trials, an effect observed in males, but not females. Contextual fear learning was largely intact, although a subset of animals in each sex were differentially affected by shock-silencing. Taken together, the results show that shock encoding in the ventral hippocampus modulates the expression of learned fear in a sex-specific manner. [ABSTRACT FROM AUTHOR]

Memory deficits are a prevalent and pervasive comorbidity of epilepsy that significantly decrease an individual's quality of life. Numerous studies have investigated the effects of a seizure on the encoding process of memory; however, few studies have assessed the effect of a seizure on the reconsolidation process of memory. We investigated how a single seizure affects memory reconsolidation in C57BL/6 J adult mice using a predominately hippocampal-dependent paradigm. Mice were presented with a tone (conditioned stimulus), that was proceeded by a mild shock (unconditioned stimulus) occurring 20 s after the tone. Three days later, a flurothyl-induced seizure was administered 1-h before a memory reconsolidation trial. The learned association was assessed by presenting a conditioned stimulus in a new context 24 h or 1-week after memory reconsolidation. We found that there were no differences in memory present between seizure and control mice at the 24 h or 1-week timepoints. Wheel running was also assessed to ensure that the seizure did not alter locomotion and bias the measure in the memory task. No differences in locomotion between seizure and control mice were observed at any timepoint. Altogether, these findings suggest that hippocampal dependent memory reconsolidation is resistant to flurothyl-induced seizure disruption. [Display omitted] • A flurothyl seizure does not disrupt hippocampal memory reconsolidation acutely. • A flurothyl seizure does not affect hippocampal reconsolidation chronically. • A flurothyl-induced seizure does not result in locomotor impairment. [ABSTRACT FROM AUTHOR]

Abstract: While a number of early studies demonstrated that hippocampal damage attenuates the expression of recent, but not remotely trained tasks, an emerging body of evidence has shown that damage to, or inactivation of, the hippocampus often impairs recall across a wide range of training–testing intervals. Collectively, these data suggest that the time course of hippocampal involvement in the storage or recall of previously-acquired memories may differ according to hippocampal subregion and the particular learning task under consideration. The present study examined the contributions of dorsal (DH) and ventral (VH) hippocampus to the expression of previously-acquired trace fear conditioning, a form of Pavlovian conditioning in which the offset of an initially neutral cue or cues and the onset of an aversive stimulus is separated by a temporal (trace) interval. Specifically, either saline or the GABA-A agonist muscimol was infused into DH or VH prior to testing either 1, 7, 28, or 42days after trace fear conditioning. The results revealed a marked dissociation: pre-testing inactivation of DH failed to impair performance at any time-point, while pre-testing inactivation of VH impaired performance at all time-points. Importantly, pre-testing inactivation of VH had no effect on the performance of previously-acquired delay conditioning, suggesting that the deficits observed in trace conditioning cannot be attributed to a deficit in performance of the freezing response. Collectively, these data suggest that VH, but not DH, remains a neuroanatomical locus critical to the recall or expression of trace fear conditioning over an extended period of time. [Copyright &y& Elsevier]

Abstract: The Coffin–Lowry syndrome (CLS) is a syndromic form of intellectual disability caused by loss-of-function of the RSK2 serine/threonine kinase encoded by the rsk2 gene. Rsk2 knockout mice, a murine model of CLS, exhibit spatial learning and memory impairments, yet the underlying neural mechanisms are unknown. In the current study, we examined the performance of Rsk2 knockout mice in cued, trace and contextual fear memory paradigms and identified selective deficits in the consolidation and reconsolidation of hippocampal-dependent fear memories as task difficulty and hippocampal demand increase. Electrophysiological, biochemical and electron microscopy analyses were carried out in the dentate gyrus of the hippocampus to explore potential alterations in neuronal functions and structure. In vivo and in vitro electrophysiology revealed impaired synaptic transmission, decreased network excitability and reduced AMPA and NMDA conductance in Rsk2 knockout mice. In the absence of RSK2, standard measures of short-term and long-term potentiation (LTP) were normal, however LTP-induced CREB phosphorylation and expression of the transcription factors EGR1/ZIF268 were reduced and that of the scaffolding protein SHANK3 was blocked, indicating impaired activity-dependent gene regulation. At the structural level, the density of perforated and non-perforated synapses and of multiple spine boutons was not altered, however, a clear enlargement of spine neck width and post-synaptic densities indicates altered synapse ultrastructure. These findings show that RSK2 loss-of-function is associated in the dentate gyrus with multi-level alterations that encompass modifications of glutamate receptor channel properties, synaptic transmission, plasticity-associated gene expression and spine morphology, providing novel insights into the mechanisms contributing to cognitive impairments in CLS. [Copyright &y& Elsevier]

In rodents, voluntary exercise and environmental complexity increases hippocampal neurogenesis and reverses spatial learning and long-term potentiation deficits in animals prenatally exposed to alcohol. The present experiment extended these findings to neonatal alcohol exposure and to delay, trace, and contextual fear conditioning. Rats were administered either 5.25 g/kg/day alcohol via gastric intubation or received sham-intubations (SI) between Postnatal Day (PD) 4 and 9 followed by either free access to a running wheel on PD 30-41 and housing in a complex environment on PD 42-72 (wheel-running plus environmental complexity; WREC) or conventional social housing (SHSH) from PD 30 to 72. Adult rats (PD 80 ± 5) received 5 trials/day of a 10-s flashing-light conditioned stimulus (CS) paired with .8 mA footshock either immediately (delay conditioning) or after a 10-s trace interval (trace conditioning) for 2 days. Neonatal alcohol exposure impaired context and trace conditioning, but not short-delay conditioning. The WREC intervention did not reverse these deficits, despite increasing context-related freezing in ethanol-exposed and SI animals. © 2012 Wiley Periodicals, Inc. Dev Psychobiol 55: 483-495, 2013 [ABSTRACT FROM AUTHOR]

Abstract: The basic helix-loop-helix (bHLH) transcription factor TCF4 was confirmed in the combined analysis of several large genome-wide association studies (GWAS) as one of the rare highly replicated significant schizophrenia (SZ) susceptibility genes in large case-control cohorts. Focused genetic association studies showed that TCF4 influences verbal learning and memory, and modulates sensorimotor gating. Mice overexpressing Tcf4 in the forebrain (Tcf4tg) display cognitive deficits in hippocampus-dependent learning tasks and impairment of prepulse inhibition, a well-established endophenotype of SZ. The spectrum of cognitive deficits in SZ subjects, however, is broad and covers attention, working memory, and anticipation. Collectively, these higher order cognitive processes and the recall of remote memories are thought to depend mainly on prefrontal cortical networks. To further investigate cognitive disturbances in Tcf4tg mice, we employed the trace fear conditioning paradigm that requires attention and critically depends on the anterior cingulate cortex (ACC). We show that Tcf4tg mice display deficits in recent and remote trace fear memory and are impaired at anticipating aversive stimuli. We also assessed mRNA expression of the neuronal activity-regulated gene Fos in the ACC and hippocampus. Upon trace conditioning, Fos expression is reduced in Tcf4tg mice as compared to controls, which parallels cognitive impairments in this learning paradigm. Collectively, these data indicate that the reduced cognitive performance in Tcf4tg mice includes deficits at the level of attention and behavioral anticipation. [Copyright &y& Elsevier]

Abstract: Cognitive flexibility is critical for survival and reflects the malleability of the central nervous system (CNS) in response to changing environmental demands. Normal aging results in difficulties modifying established behaviors, which may involve medial prefrontal cortex (mPFC) dysfunction. Using extinction of conditioned fear in rats to assay cognitive flexibility, we demonstrate that extinction deficits reminiscent of mPFC dysfunction first appear during middle age, in the absence of hippocampus-dependent context deficits. Emergence of aging-related extinction deficits paralleled a redistribution of neuronal excitability across two critical mPFC regions via two distinct mechanisms. First, excitability decreased in regular spiking neurons of infralimbic-mPFC (IL), a region whose activity is required for extinction. Second, excitability increased in burst spiking neurons of prelimbic-mPFC (PL), a region whose activity hinders extinction. Experiments using synaptic blockers revealed that these aging-related differences were intrinsic. Thus, changes in IL and PL intrinsic excitability may contribute to cognitive flexibility impairments observed during normal aging. [Copyright &y& Elsevier]

Persistent-firing neurons in the entorhinal cortex (EC) and the lateral nucleus of the amygdala (LA) continue to discharge long after the termination of the original, spike-initiating current. An emerging theory proposes that endogenous persistent firing helps support a transient memory system. This study demonstrated that persistent-firing neurons are also prevalent in rat perirhinal cortex (PR), which lies immediately adjacent to and is reciprocally connected with EC and LA. Several characteristics of persistent-firing neurons in PR were similar to those previously reported in LA and EC. Persistent firing in PR was enabled by the application of carbachol, a nonselective cholinergic agonist, and it was induced by injecting a suprathreshold current or by stimulating suprathreshold excitatory synaptic inputs to the neuron. Once induced, persistent firing lasted for seconds to minutes. Persistent firing could always be terminated by a sufficiently large and prolonged hyperpolarizing current; it was prevented by antagonists of muscarinic cholinergic receptors (mAChRs); and it was blocked by flufenamic acid. The latter has been suggested to inhibit a Ca2+-activated nonspecific cation conductance ( GCAN) that normally furnishes the sustained depolarization during persistent firing. In many PR neurons, the discharge rate during persistent firing was a graded function of depolarizing and/or hyperpolarizing inputs. Persistent firing was not prevented by blocking fast excitatory and inhibitory synaptic transmission, demonstrating that it can be generated endogenously. We suggest that persistent-firing neurons in PR, EC, LA, and certain other brain regions may cooperate in support of a transient-memory system. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Abstract: Trace fear conditioning, in which a brief empty “trace interval” occurs between presentation of the CS and UCS, differs from standard delay conditioning in that contributions from both the hippocampus and prelimbic medial prefrontal cortex (PL mPFC) are required to form a normal long term memory. Little is currently known about how the PL interacts with various temporal lobe structures to support learning across this temporal gap between stimuli. We temporarily inactivated PL along with either ventral hippocampus or amygdala in a disconnection design to determine if these structures functionally interact to acquire trace fear conditioning. Disconnection (contralateral injections) of the PL with either the ventral hippocampus or amygdala impaired trace fear conditioning; however, ipsilateral control rats were also impaired. Follow-up experiments examined the effects of unilateral inactivation of the PL, ventral hippocampus, or amygdala during conditioning. The results of this study demonstrate that unilateral inactivation of the ventral hippocampus or amygdala impairs memory, while bilateral inactivation of the PL is required to produce a deficit. Memory deficits after unilateral inactivation of the ventral hippocampus or amygdala prevent us from determining whether the mPFC functionally interacts with the medial temporal lobe using a disconnection approach. Nonetheless, our findings suggest that the trace fear network is more integrated than previously thought. [Copyright &y& Elsevier]

Abstract: Accumulations of β-amyloid (Aβ) contribute to neurological deficits associated with Alzheimer''s disease (AD). The effects of Aβ on basal neuronal excitability and learning-related AHP plasticity were examined using whole-cell recordings from hippocampal neurons in the 5XFAD mouse model of AD. A robust increase in Aβ42 (and elevated levels of Aβ38–40) in naïve 5XFAD mice was associated with decreased basal neuronal excitability, evidenced by a select increase in Ca2+-sensitive afterhyperpolarization (AHP). Moreover, trace fear deficits observed in a subset of 5XFAD weak-learner mice were associated with a greater enhancement of the AHP in neurons, as compared to age-matched 5XFAD learner and 5XFAD naïve mice. Importantly, learning-related plasticity of the AHP remained intact in a subset of 5XFAD mice that learned trace fear conditioning to a set criterion. We show that APP-PS1 mutations enhance Aβ and disrupt basal excitability via a Ca2+-dependent enhancement of the AHP, and suggest disruption to learning-related modulation of intrinsic excitability resulted, in part, from altered cholinergic modulation of the AHP in the 5XFAD mouse model of AD (170 of 170). [Copyright &y& Elsevier]

Abstract: Although cholinergic mechanisms have been widely implicated in learning and memory processes, few studies have investigated the specific contribution of hippocampal cholinergic transmission during trace fear conditioning, a form of associative learning involving a temporal gap between two stimuli. Microinfusions of scopolamine, a muscarinic receptor antagonist, into the dorsal hippocampus (DH) produced dose-dependent impairment in the acquisition and expression of a conditioned response (CR) following trace fear conditioning with a tone conditioned stimulus (CS) and a footshock unconditioned stimulus (US) in rats. The same infusions, however, had no effect on delay conditioning, general activity, pain sensitivity or attentional modulation. Moreover, scopolamine infusions attenuated phosphorylation of extracellular signal-regulated kinase (ERK) in the amygdala, indicating that cholinergic signals in the DH are important for trace fear conditioning. Taken together, the current study provides evidence that cholinergic neurotransmission in the DH is essential for the cellular processing of CS–US association in the amygdala when the two stimuli are temporally disconnected. [ABSTRACT FROM AUTHOR]

Abstract: The effects of genetic background on fear trace conditioning were evaluated in relation to phosphorylated levels of cAMP response element-binding protein (CREB) in the hippocampus using two different inbred strains of mice, C57BL/6 and DBA/2. The male mice received a trace fear conditioning protocol and unpaired control groups were included to assess nonassociative effects on test performance. Both C57BL/6 and DBA/2 mice with paired training displayed higher freezing responses during testing than those with unpaired training, respectively. The C57BL/6 mice with paired training also displayed higher freezing responses to the tone-CS during testing than the DBA/2 mice with paired training. Because much evidence implicates the hippocampus as an important neural substrate for trace fear conditioning, the engagement of the hippocampus was examined after testing by measuring levels of CREB and phosphorylated CREB (pCREB). The results revealed that hippocampal CREB levels in both strains of mice were not significantly altered according to the type of training (unpaired vs. paired). However, the hippocampal pCREB levels were significantly higher in the paired training group than the unpaired control group in C57BL/6 mice, but not in DBA/2 mice. These findings indicate that hippocampal pCREB is closely tied to this form of associative conditioning only in C57BL/6 mice and that different neural substrates may support trace conditioning in C57BL/6 and DBA/2 strains. [Copyright &y& Elsevier]