Adult alcohol drinking and emotional tone are mediated by neutral sphingomyelinase during development in males.

Alcohol use, abuse, and addiction, and resulting health hazards are highly sex-dependent with unknown mechanisms. Previously, strong links between the SMPD3 gene and its coded protein neutral sphingomyelinase 2 (NSM) and alcohol abuse, emotional behavior, and bone defects were discovered and multiple mechanisms were identified for females. Here we report strong sex-dimorphisms for central, but not for peripheral mechanisms of NSM action in mouse models. Reduced NSM activity resulted in enhanced alcohol consumption in males, but delayed conditioned rewarding effects. It enhanced the acute dopamine response to alcohol, but decreased monoaminergic systems adaptations to chronic alcohol. Reduced NSM activity increased depression- and anxiety-like behavior, but was not involved in alcohol use for the self-management of the emotional state. Constitutively reduced NSM activity impaired structural development in the brain and enhanced lipidomic sensitivity to chronic alcohol. While the central effects were mostly opposite to NSM function in females, similar roles in bone-mediated osteocalcin release and its effects on alcohol drinking and emotional behavior were observed. These findings support the view that the NSM and multiple downstream mechanism may be a source of the sex-differences in alcohol use and emotional behavior.

The 5-HT1A receptor agonist 8-OH-DPAT modulates motor/exploratory activity, recognition memory and dopamine transporter binding in the dorsal and ventral striatum.

In the present studies, we assessed the effect of the 5-HT1A receptor (R) agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on motor and exploratory behaviors, object and place recognition and dopamine transporter (DAT) and serotonin transporter (SERT) binding in the rat brain. In Experiment I, motor/exploratory behaviors were assessed in an open field after injection of either 8-OH-DPAT (0.1 and 3 mg/kg) or vehicle for 30 min without previous habituation to the open field. In Experiment II, rats underwent a 5-min exploration trial in an open field with two identical objects. After injection of either 8-OH-DPAT (0.1 and 3 mg/kg) or vehicle, rats underwent a 5-min test trial with one of the objects replaced by a novel one and the other object transferred to a novel place. Subsequently, N-o-fluoropropyl-2b-carbomethoxy-3b-(4-[123I]iodophenyl)-nortropane ([123I]FP-CIT; 11 ± 4 MBq) was injected into the tail vein. Regional radioactivity accumulations were determined post mortem with a well counter. In both experiments, 8-OH-DPAT dose-dependently increased ambulation and exploratory head-shoulder motility, whereas rearing was dose-dependently decreased. In the test rial of Experiment II, there were no effects of 8-OH-DPAT on overall activity, sitting and grooming. 8-OH-DPAT dose-dependently impaired recognition of object and place. 8-OH-DPAT (3 mg/kg) increased DAT binding in the dorsal striatum relative to both vehicle and 0.1 mg/kg 8-OH-DPAT. Furthermore, in the ventral striatum, DAT binding was decreased after 3 mg/kg 8-OH-DPAT relative to vehicle. Findings indicate that motor/exploratory behaviors, memory for object and place and regional dopamine function may be modulated by the 5-HT1AR. Since, after 8-OH-DPAT, rats exhibited more horizontal and less (exploratory) vertical motor activity, while overall activity was not different between groups, it may be inferred, that the observed impairment of object recognition was not related to a decrease of motor activity as such, but to a decrease of intrinsic motivation, attention and/or awareness, which are relevant accessories of learning. Furthermore, the present findings on 8-OH-DPAT action indicate associations not only between motor/exploratory behavior and the recognition of object and place but also between the respective parameters and the levels of available DA in dorsal and ventral striatum.

Neutral sphingomyelinase mediates the co-morbidity trias of alcohol abuse, major depression and bone defects.

Mental disorders are highly comorbid and occur together with physical diseases, which are often considered to arise from separate pathogenic pathways. We observed in alcohol-dependent patients increased serum activity of neutral sphingomyelinase. A genetic association analysis in 456,693 volunteers found associations of haplotypes of SMPD3 coding for NSM-2 (NSM) with alcohol consumption, but also with affective state, and bone mineralisation. Functional analysis in mice showed that NSM controls alcohol consumption, affective behaviour, and their interaction by regulating hippocampal volume, cortical connectivity, and monoaminergic responses. Furthermore, NSM controlled bone-brain communication by enhancing osteocalcin signalling, which can independently supress alcohol consumption and reduce depressive behaviour. Altogether, we identified a single gene source for multiple pathways originating in the brain and bone, which interlink disorders of a mental-physical co-morbidity trias of alcohol abuse-depression/anxiety-bone disorder. Targeting NSM and osteocalcin signalling may, thus, provide a new systems approach in the treatment of a mental-physical co-morbidity trias.

Neutral Sphingomyelinase is an Affective Valence-Dependent Regulator of Learning and Memory.

Sphingolipids and enzymes of the sphingolipid rheostat determine synaptic appearance and signaling in the brain, but sphingolipid contribution to normal behavioral plasticity is little understood. Here we asked how the sphingolipid rheostat contributes to learning and memory of various dimensions. We investigated the role of these lipids in the mechanisms of two different types of memory, such as appetitively and aversively motivated memory, which are considered to be mediated by different neural mechanisms. We found an association between superior performance in short- and long-term appetitively motivated learning and regionally enhanced neutral sphingomyelinase (NSM) activity. An opposite interaction was observed in an aversively motivated task. A valence-dissociating role of NSM in learning was confirmed in mice with genetically reduced NSM activity. This role may be mediated by the NSM control of N-methyl-d-aspartate receptor subunit expression. In a translational approach, we confirmed a positive association of serum NSM activity with long-term appetitively motivated memory in nonhuman primates and in healthy humans. Altogether, these data suggest a new sphingolipid mechanism of de-novo learning and memory, which is based on NSM activity.

Functional Convergence of Motor and Social Processes in Lobule IV/V of the Mouse Cerebellum.

Topographic organization of the cerebellum is largely segregated into the anterior and posterior lobes that represent its "motor" and "non-motor" functions, respectively. Although patients with damage to the anterior cerebellum often exhibit motor deficits, it remains unclear whether and how such an injury affects cognitive and social behaviors. To address this, we perturbed the activity of major anterior lobule IV/V in mice by either neurotoxic lesion or chemogenetic excitation of Purkinje cells in the cerebellar cortex. We found that both of the manipulations impaired motor coordination, but not general locomotion or anxiety-related behavior. The lesioned animals showed memory deficits in object recognition and social-associative recognition tests, which were confounded by a lack of exploration. Chemogenetic excitation of Purkinje cells disrupted the animals' social approach in a less-preferred context and social memory, without affecting their overall exploration and object-based memory. In a free social interaction test, the two groups exhibited less interaction with a stranger conspecific. Subsequent c-Fos imaging indicated that decreased neuronal activities in the medial prefrontal cortex, hippocampal dentate gyrus, parahippocampal cortices, and basolateral amygdala, as well as disorganized modular structures of the brain networks might underlie the reduced social interaction. These findings suggest that the anterior cerebellum plays an intricate role in processing motor, cognitive, and social functions.

Intranasal pregnenolone increases acetylcholine in frontal cortex, hippocampus, and amygdala-Preferentially in the hemisphere ipsilateral to the injected nostril.

This study determined the effects of intranasal pregnenolone (IN-PREG) on acetylcholine (ACh) levels in selected areas of the rat brain, using in vivo microdialysis. Previous studies showed that PREG rapidly reaches the rodent brain after intranasal administration and that direct infusion of PREG and PREG-S into the basal forebrain modulates ACh release in frontal cortex, amygdala, and hippocampus. In the present study, we investigated the effects of IN-PREG on the cholinergic system in the rat brain. In the first experiment, IN-PREG (5.6 and 11.2 mg/ml) or vehicle was applied bilaterally, and we hypothesized that IN-PREG would increase ACh levels in amygdala, hippocampus, and frontal cortex, relative to baseline and vehicle. Dialysate was collected for 100 min, based on pilot data of duration of effect. Bilateral IN-PREG (5.6 and 11.2 mg/ml) increased frontal cortex and hippocampal ACh relative to both baseline and vehicle. Moreover, 11.2 mg/ml PREG increased ACh in the amygdala relative to baseline, the lower dose, and vehicle. Therefore, in the second experiment, IN-PREG (11.2 mg/ml) was applied only into one nostril, with vehicle applied into the other nostril, in order to determine whether ACh is predominantly increased in the ipsilateral relative to the contralateral amygdala. Unilateral application of IN-PREG increased ACh in the ipsilateral amygdala, whereas no effect was observed on the contralateral side, suggesting that PREG was transported from the nostrils to the brain via the olfactory epithelial pathway, but not by circulation. The present data provide additional information on IN-PREG action in the cholinergic system of frontal cortex, amygdala, and hippocampus. This may be relevant for therapeutic IN application of PREG in neurogenerative and neuropsychiatric disorders.

Behavioral Resilience and Sensitivity to Locally Restricted Cortical Migration Deficits Induced by In Utero Knockdown of Disabled-1 in the Adult Rat.

Irregular neuronal migration plays a causal role in mental illnesses such as schizophrenia and autism, but the very nature of the migration deficits necessary to evoke adult behavioral changes is unknown. Here, we used in utero electroporation (IUE) in rats to induce a locally restricted, cortical migration deficit by knockdown of disabled-1 (Dab1), an intracellular converging point of the reelin pathway. After birth, selection of successfully electroporated rats by detection of in vivo bioluminescence of a simultaneously electroporated luciferase gene correlated to and was thus predictive to the number of electroporated neurons in postmortem histochemistry at 6 months of age. Rat neurons silenced for Dab1 did not migrate properly and their number surprisingly decreased after E22. Behavioral tests at adult ages (P180) revealed increased sensitivity to amphetamine as well as decreased habituation, but no deficits in memory tasks or motor functions. The data suggest that even subtle migration deficits involving only ten-thousands of cortical neurons during neurodevelopment can lead to lasting behavioral and neuronal changes into adulthood in some very specific behavioral domains. On the other hand, the lack of effects on various memory-related tasks may indicate resilience and plasticity of cognitive functions critical for survival under these specific conditions.

Effects of EMF emissions from undersea electric cables on coral reef fish.

The objective of this study was to determine if electromagnetic field (EMF) emissions from undersea power cables impacted local marine life, with an emphasis on coral reef fish. The work was done at the South Florida Ocean Measurement Facility of Naval Surface Warfare Center in Broward County, Florida, which has a range of active undersea detection and data transmission cables. EMF emissions from a selected cable were created during non-destructive visual fish surveys on SCUBA. During surveys, the transmission of either alternating current (AC), direct current (DC), or none (OFF) was randomly initiated by the facility at a specified time. Visual surveys were conducted using standardized transect and point-count methods to acquire reef fish abundances and species richness prior to and immediately after a change in transmission frequency. The divers were also tasked to note the reaction of the reef fish to the immediate change in EMF during a power transition. In general, analysis of the data did not find statistical differences among power states and any variables. However, this may be a Type II error as there are strong indications of a potential difference of a higher abundance of reef fish at the sites when the power was off, and further study is warranted. Bioelectromagnetics. 39:35-52, 2018. © 2017 Wiley Periodicals, Inc.

Interaction between the medial prefrontal cortex and hippocampal CA1 area is essential for episodic-like memory in rats.

The interplay between medial prefrontal cortex (mPFC) and hippocampus, particularly the hippocampal CA3 area, is critical for episodic memory. To what extent the mPFC also interacts with the hippocampus CA1 subregion still requires elucidation. To investigate this issue, male rats received unilateral N-methyl-D-aspartate lesions of the mPFC together with unilateral lesions of the hippocampal CA1 area, either in the same (control) or in the opposite hemispheres (disconnection). They underwent an episodic-like memory test, combining what-where-when information, and separate tests for novel object preference (what), object place preference (where) and temporal order memory (when). Compared to controls, the disconnected mPFC-CA1 rats exhibited disrupted episodic-like memory with an impaired integration of the what-where-when elements. Both groups showed intact memories for what and when, while only the control group showed intact memory for where. These findings suggest that the functional interaction of the mPFC-CA1 circuit is crucial for the processing of episodic memory and, in particular, for the integration of the spatial memory component.

Intra-nasal dopamine alleviates cognitive deficits in tgDISC1 rats which overexpress the human DISC1 gene.

The Disrupted-in-Schizophrenia 1 (DISC1) gene has been associated with mental illnesses such as major depression and schizophrenia. The transgenic DISC1 (tgDISC1) rat, which overexpresses the human DISC1 gene, is known to exhibit deficient dopamine (DA) homeostasis. To ascertain whether the DISC1 gene also impacts cognitive functions, 14-15 months old male tgDISC1 rats and wild-type controls were subjected to the novel object preference (NOP) test and the object-based attention test (OBAT) in order to assess short-term memory (1 h), long-term memory (24 h), and attention. RESULTS: The tgDISC1 group exhibited intact short-term memory, but deficient long-term-memory in the NOP test and deficient attention-related behavior in the OBAT. In a different group of tgDISC1 rats, 3 mg/kg intranasally applied dopamine (IN-DA) or its vehicle was applied prior to the NOP or the OBAT test. IN-DA reversed cognitive deficits in both the NOP and OBAT tests. In a further cohort of tgDISC1 rats, post-mortem levels of DA, noradrenaline, serotonin and acetylcholine were determined in a variety of brain regions. The tgDISC1 group had less DA in the neostriatum, hippocampus and amygdala, less acetylcholine in neostriatum, nucleus accumbens, hippocampus, and amygdala, more serotonin in the nucleus accumbens, and less serotonin and noradrenaline in the amygdala. CONCLUSIONS: Our findings show that DISC1 overexpression and misassembly is associated with deficits in long-term memory and attention-related behavior. Since behavioral impairments in tgDISC1 rats were reversed by IN-DA, DA deficiency may be a major cause for the behavioral deficits expressed in this model.

Amyloid-ß dimers in the absence of plaque pathology impair learning and synaptic plasticity.

Despite amyloid plaques, consisting of insoluble, aggregated amyloid-ß peptides, being a defining feature of Alzheimer's disease, their significance has been challenged due to controversial findings regarding the correlation of cognitive impairment in Alzheimer's disease with plaque load. The amyloid cascade hypothesis defines soluble amyloid-ß oligomers, consisting of multiple amyloid-ß monomers, as precursors of insoluble amyloid-ß plaques. Dissecting the biological effects of single amyloid-ß oligomers, for example of amyloid-ß dimers, an abundant amyloid-ß oligomer associated with clinical progression of Alzheimer's disease, has been difficult due to the inability to control the kinetics of amyloid-ß multimerization. For investigating the biological effects of amyloid-ß dimers, we stabilized amyloid-ß dimers by an intermolecular disulphide bridge via a cysteine mutation in the amyloid-ß peptide (Aß-S8C) of the amyloid precursor protein. This construct was expressed as a recombinant protein in cells and in a novel transgenic mouse, termed tgDimer mouse. This mouse formed constant levels of highly synaptotoxic soluble amyloid-ß dimers, but not monomers, amyloid-ß plaques or insoluble amyloid-ß during its lifespan. Accordingly, neither signs of neuroinflammation, tau hyperphosphorylation or cell death were observed. Nevertheless, these tgDimer mice did exhibit deficits in hippocampal long-term potentiation and age-related impairments in learning and memory, similar to what was observed in classical Alzheimer's disease mouse models. Although the amyloid-ß dimers were unable to initiate the formation of insoluble amyloid-ß aggregates in tgDimer mice, after crossbreeding tgDimer mice with the CRND8 mouse, an amyloid-ß plaque generating mouse model, Aß-S8C dimers were sequestered into amyloid-ß plaques, suggesting that amyloid-ß plaques incorporate neurotoxic amyloid-ß dimers that by themselves are unable to self-assemble. Our results suggest that within the fine interplay between different amyloid-ß species, amyloid-ß dimer neurotoxic signalling, in the absence of amyloid-ß plaque pathology, may be involved in causing early deficits in synaptic plasticity, learning and memory that accompany Alzheimer's disease.

Evidence for a Specific Integrative Mechanism for Episodic Memory Mediated by AMPA/kainate Receptors in a Circuit Involving Medial Prefrontal Cortex and Hippocampal CA3 Region.

We asked whether episodic-like memory requires neural mechanisms independent of those that mediate its component memories for "what," "when," and "where," and if neuronal connectivity between the medial prefrontal cortex (mPFC) and the hippocampus (HPC) CA3 subregion is essential for episodic-like memory. Unilateral lesion of the mPFC was combined with unilateral lesion of the CA3 in the ipsi- or contralateral hemispheres in rats. Episodic-like memory was tested using a task, which assesses the integration of memories for "what, where, and when" concomitantly. Tests for novel object recognition (what), object place (where), and temporal order memory (when) were also applied. Bilateral disconnection of the mPFC-CA3 circuit by N-methyl-d-aspartate (NMDA) lesions disrupted episodic-like memory, but left the component memories for object, place, and temporal order, per se, intact. Furthermore, unilateral NMDA lesion of the CA3 plus injection of (6-cyano-7-nitroquinoxaline-2,3-dione) (CNQX) (AMPA/kainate receptor antagonist), but not AP-5 (NMDA receptor antagonist), into the contralateral mPFC also disrupted episodic-like memory, indicating the mPFC AMPA/kainate receptors as critical for this circuit. These results argue for a selective neural system that specifically subserves episodic memory, as it is not critically involved in the control of its component memories for object, place, and time.

A sphingolipid mechanism for behavioral extinction.

Reward-dependent instrumental behavior must continuously be re-adjusted according to environmental conditions. Failure to adapt to changes in reward contingencies may incur psychiatric disorders like anxiety and depression. When an expected reward is omitted, behavior undergoes extinction. While extinction involves active re-learning, it is also accompanied by emotional behaviors indicative of frustration, anxiety, and despair (extinction-induced depression). Here, we report evidence for a sphingolipid mechanism in the extinction of behavior. Rapid extinction, indicating efficient re-learning, coincided with a decrease in the activity of the enzyme acid sphingomyelinase (ASM), which catalyzes turnover of sphingomyelin to ceramide, in the dorsal hippocampus of rats. The stronger the decline in ASM activity, the more rapid was the extinction. Sphingolipid-focused lipidomic analysis showed that this results in a decline of local ceramide species in the dorsal hippocampus. Ceramides shape the fluidity of lipid rafts in synaptic membranes and by that way can control neural plasticity. We also found that aging modifies activity of enzymes and ceramide levels in selective brain regions. Aging also changed how the chronic treatment with corticosterone (stress) or intranasal dopamine modified regional enzyme activity and ceramide levels, coinciding with rate of extinction. These data provide first evidence for a functional ASM-ceramide pathway in the brain involved in the extinction of learned behavior. This finding extends the known cellular mechanisms underlying behavioral plasticity to a new class of membrane-located molecules, the sphingolipids, and their regulatory enzymes, and may offer new treatment targets for extinction- and learning-related psychopathological conditions. Sphingolipids are common lipids in the brain which form lipid domains at pre- and postsynaptic membrane compartments. Here we show a decline in dorsal hippocampus ceramide species together with a reduction of acid sphingomyelinase activity during extinction of conditioned behavior in rats. This reduction was associated with expression of re-learning-related behavior, but not with emotional behaviors. Read the Editorial Highlight for this article on page 485.

The medial prefrontal cortex-lateral entorhinal cortex circuit is essential for episodic-like memory and associative object-recognition.

The prefrontal cortex directly projects to the lateral entorhinal cortex (LEC), an important substrate for engaging item-associated information and relaying the information to the hippocampus. Here we ask to what extent the communication between the prefrontal cortex and LEC is critically involved in the processing of episodic-like memory. We applied a disconnection procedure to test whether the interaction between the medial prefrontal cortex (mPFC) and LEC is essential for the expression of recognition memory. It was found that male rats that received unilateral NMDA lesions of the mPFC and LEC in the same hemisphere, exhibited intact episodic-like (what-where-when) and object-recognition memories. When these lesions were placed in the opposite hemispheres (disconnection), episodic-like and associative memories for object identity, location and context were impaired. However, the disconnection did not impair the components of episodic memory, namely memory for novel object (what), object place (where) and temporal order (when), per se. Thus, the present findings suggest that the mPFC and LEC are a critical part of a neural circuit that underlies episodic-like and associative object-recognition memory.

Concurrent assessment of memory for object and place: Evidence for different preferential importance of perirhinal cortex and hippocampus and for promnestic effect of a neurokinin-3 R agonist.

We here explore the utility of a paradigm that allows the simultaneous assessment of memory for object (what) and object location (where) and their comparative predominance. Two identical objects are presented during a familiarity trial; during the test trial one of these is displaced, and a new object is presented in a familiar location. When tested 5 or 80min later, rats explored both the novel and the displaced objects more than two familiar stationary objects, indicating intact memory for both, object and place. When tested 24h later rats explored the novel object more than the displaced familiar one, suggesting that forgetting differently influenced object and place memory, with memory for object being more robust than memory for place. Animals that received post-trial administration of the neurokinin-3 receptor agonist senktide and were tested 24h later, now explored the novel and displaced objects equally, suggesting that the treatment prevented the selective decay of memory for location. Next, animals received NMDA lesions in either the perirhinal cortex or the hippocampus, which are hypothesized to be preferentially involved in memory for objects and memory for place, respectively. When tested 5 or 80min later, the perirhinal cortex lesion group explored the displaced object more, indicating relatively deficient object memory, while the hippocampal lesion led to the opposite pattern, demonstrating comparatively deficient place memory. These results suggest different preferential engagement of the perirhinal cortex and hippocampus in their processing of memory for object and place. This preference test lends itself to application in the comparison of selective lesions of neural sites and projection systems as well as to the assessment of possible preferential action of pharmacological agents on neurochemical processes that subserve object vs place learning.

Promnestic effects of intranasally applied pregnenolone in rats.

The neurosteroid pregnenolone (PREG) has been shown to have memory-enhancing and anti-depressant action. The present study addresses the question of whether intranasally applied pregnenolone (IN-PREG) also has promnestic properties in the rat. We examined the effects of IN-PREG at doses of 0.187 and 0.373mg/kg on memory for objects and their location on learning and retention of escape in a water maze, and on behavior on the elevated plus maze. The main findings were: (a) Pre-trial, but not post-trial, administration of IN-PREG facilitated long-term memory in a novel object-preference test and a novel object-location preference test when tested 48h after dosing. (b) Over the duration of 5days of extinction trials, after learning to escape onto a hidden platform in a water maze, the animals treated with IN-PREG spent more time in searching for the absent platform, indicating either, or both, superior memory for the former position of the escape platform, or a higher resistance to extinction. (c) Administration of the anticholinergic, scopolamine, disrupted learning to escape from the water maze in the vehicle-treated group. The IN-PREG treated groups exhibited superior escape learning in comparison with vehicle controls, indicating that the treatment countered the scopolamine effect. IN-PREG treatment had no influence on behaviors on the elevated plus maze. Our results demonstrate that IN-PREG is behaviorally active with cognitive enhancing properties comparable to those known from studies employing systemic PREG administration.

DAT versus D2 receptor binding in the rat striatum: l-DOPA-induced motor activity is better predicted by reuptake than release of dopamine.

The reuptake and release of dopamine (DA) can be estimated using in vivo imaging methods by assessing the competition between endogenous DA and an administered exogenous DA transporter (DAT) and D2 receptor (D2 R) radioligand, respectively. The aim of this study was to investigate the comparative roles of DA release vs DA reuptake in the rat striatum with small animal SPECT in relation to l-DOPA-induced behaviors. DAT and D2 R binding, together with behavioral measures, were obtained in 99 rats in response to treatment with either 5 or 10 mg/kg l-DOPA or vehicle. The behavioral parameters included the distance travelled, and durations and frequencies of ambulation, sitting, rearing, head-shoulder motility, and grooming. Data were subjected to a cluster analysis and to a multivariate principal component analysis. The highest DAT binding (i.e., the lowest DA reuptake) was associated with the highest, and the lowest DAT binding (i.e., the highest DA reuptake) was associated with the lowest motor/exploratory activity. The highest and the lowest D2 R binding (i.e., the lowest and the highest DA release, respectively) were merely associated with the second highest and second lowest levels of motor/exploratory activity. These findings indicate that changes in DA reuptake in response to fluctuating DA levels offer a better prediction of motor activity than the release of DA into the synaptic cleft. This dissociation, as reflected by in vivo DAT and D2 R binding data, may be accounted for by the regulatory sensitization meachnisms that occur at D2 R binding sites in response to altered levels of DA. Synapse 70:369-377, 2016. © 2016 Wiley Periodicals, Inc.

Chronic corticosterone treatment enhances extinction-induced depression in aged rats.

Withdrawal and avoidance behavior are common symptoms of depression and can appear as a consequence of absence of reward, i.e. extinction-induced depression (EID). This is particularly relevant for the aged organism subjected to pronounced loss of former rewards. Avoidance of the former site of reward and increased withdrawal into a distant compartment accompany extinction of food-rewarded behavior in rodent models. During extinction, behavioral markers for re-learning dissociate from indicators of extinction-induced depression. Here we examined the effect of a chronic treatment with corticosterone (CORT), a well-known inducer of depression-related behavior, on EID in adult and aged rats. Adult (3-4months) and aged (18months) male rats were treated with CORT via drinking water for 3weeks prior to extinction of a cued food-reward task. CORT treatment increased the distance from the site of reward and decreased goal tracking behavior during extinction, especially in the aged rats. Plasma hormone levels measured before and after restraint stress showed a decline in basal ACTH- and CORT-levels after chronic CORT treatment in aged animals. The treatment significantly impaired the HPA-axis activation after acute stress in both, adult and aged animals, alike. Altogether, these findings show an enhancement of EID after chronic CORT treatment in the aged organism, which may be mediated by an impaired HPA-axis sensitivity. These findings may have special relevance for the investigation of human geriatric depression.

Neurokinin3 receptor as a target to predict and improve learning and memory in the aged organism.

Impaired learning and memory performance is often found in aging as an early sign of dementia. It is associated with neuronal loss and reduced functioning of cholinergic networks. Here we present evidence that the neurokinin3 receptors (NK3-R) and their influence on acetylcholine (ACh) release may represent a crucial mechanism that underlies age-related deficits in learning and memory. Repeated pharmacological stimulation of NK3-R in aged rats was found to improve learning in the water maze and in object-place recognition. This treatment also enhanced in vivo acetylcholinergic activity in the frontal cortex, hippocampus, and amygdala but reduced NK3-R mRNA expression in the hippocampus. Furthermore, NK3-R agonism incurred a significantly higher increase in ACh levels in aged animals that showed superior learning than in those that were most deficient in learning. Our findings suggest that the induced activation of ACh, rather than basal ACh activity, is associated with superior learning in the aged. To test whether natural variation in NK3-R function also determines learning and memory performance in aged humans, we investigated 209 elderly patients with cognitive impairments. We found that of the 15 analyzed single single-nucleotide ploymorphism (SNPs) of the NK3-R-coding gene, TACR3, the rs2765 SNP predicted the degree of impairment of learning and memory in these patients. This relationship could be partially explained by a reduced right hippocampus volume in a subsample of 111 tested dementia patients. These data indicate the NK3-R as an important target to predict and improve learning and memory performance in the aged organism.

The neurokinin-3 receptor agonist senktide facilitates the integration of memories for object, place and temporal order into episodic memory.

Senktide, a potent neurokinin-3 receptor (NK3-R) agonist, has been shown to have promnestic effects in adult and aged rodents and to facilitate episodic-like memory (ELM) in mice when administrated before the learning trial. In the present study we assessed the effects of senktide on memory consolidation by administering it post-trial (after the learning trial) in adult rats. We applied an ELM test, based on the integrated memory for object, place and temporal order, which we developed (Kart-Teke, de Souza Silva, Huston, & Dere, 2006). This test involves two learning trials and one test trial. We examined intervals of 1h and 23 h between the learning and test trials (experiment 1) in untreated animals and found that they exhibited intact ELM after a delay of 1 h, but not 23 h. In another test for ELM performed 7 days later, vehicle or senktide (0.2 mg/kg, s.c.) was applied immediately after the second learning trial and the test was conducted 23 h later (experiment 2). Senktide treatment recovered components of ELM (memory for place and object) compared with vehicle-treated animals. After one more week, vehicle or senktide (0.2 mg/kg, s.c.) was applied post-trial and the test conducted 6h later (experiment 3). The senktide-treated group exhibited intact ELM, unlike the vehicle-treated group. Finally, animals received post-trial treatment with either vehicle or SR142801, a selective NK3-R antagonist (6 mg/kg, i.p.), 1 min before senktide injection (0.2 mg/kg, s.c.) in the ELM paradigm and were tested 6h later (experiment 4). The vehicle+senktide group showed intact ELM, while the SR142801+senktide group did not. The results indicate that senktide facilitated the consolidation or the expression of ELM and that the senktide effect was NK3-R dependent.