Amphetamine disrupts haemodynamic correlates of prediction errors in nucleus accumbens and orbitofrontal cortex.

In an uncertain world, the ability to predict and update the relationships between environmental cues and outcomes is a fundamental element of adaptive behaviour. This type of learning is typically thought to depend on prediction error, the difference between expected and experienced events and in the reward domain that has been closely linked to mesolimbic dopamine. There is also increasing behavioural and neuroimaging evidence that disruption to this process may be a cross-diagnostic feature of several neuropsychiatric and neurological disorders in which dopamine is dysregulated. However, the precise relationship between haemodynamic measures, dopamine and reward-guided learning remains unclear. To help address this issue, we used a translational technique, oxygen amperometry, to record haemodynamic signals in the nucleus accumbens (NAc) and orbitofrontal cortex (OFC), while freely moving rats performed a probabilistic Pavlovian learning task. Using a model-based analysis approach to account for individual variations in learning, we found that the oxygen signal in the NAc correlated with a reward prediction error, whereas in the OFC it correlated with an unsigned prediction error or salience signal. Furthermore, an acute dose of amphetamine, creating a hyperdopaminergic state, disrupted rats' ability to discriminate between cues associated with either a high or a low probability of reward and concomitantly corrupted prediction error signalling. These results demonstrate parallel but distinct prediction error signals in NAc and OFC during learning, both of which are affected by psychostimulant administration. Furthermore, they establish the viability of tracking and manipulating haemodynamic signatures of reward-guided learning observed in human fMRI studies by using a proxy signal for BOLD in a freely behaving rodent.

Oxygen responses within the nucleus accumbens are associated with individual differences in effort exertion in rats.

Goal-directed motivated behaviour is crucial for everyday life. Such behaviour is often measured, in rodents, under a progressive ratio (PR) schedule of reinforcement. Previous studies have identified a few brain structures critical for supporting PR performance. However, the association between neural activity within these regions and individual differences in effort-related behaviour is not known. Presently, we used constant potential in vivo oxygen amperometry, a surrogate for functional resonance imaging in rodents, to assess changes in tissue oxygen levels within the nucleus accumbens (NAc) and orbitofrontal cortex (OFC) in male Wistar rats performing a PR task. Within both regions, oxygen responses to rewards increased as the effort exerted to obtain the rewards was larger. Furthermore, higher individual breakpoints were associated with greater magnitude NAc oxygen responses. This association could not be explained by temporal confounds and remained significant when controlling for the different number of completed trials. Animals with higher breakpoints also showed greater magnitude NAc oxygen responses to rewards delivered independently of any behaviour. In contrast, OFC oxygen responses were not associated with individual differences in behavioural performance. The present results suggest that greater NAc oxygen responses following rewards, through a process of incentive motivation, may allow organisms to remain on task for longer and to overcome greater effort costs.

Tracking progressive pathological and functional decline in the rTg4510 mouse model of tauopathy.

BACKGROUND: The choice and appropriate use of animal models in drug discovery for Alzheimer's disease (AD) is pivotal to successful clinical translation of novel therapeutics, yet true alignment of research is challenging. Current models do not fully recapitulate the human disease, and even exhibit various degrees of regional pathological burden and diverse functional alterations. Given this, relevant pathological and functional endpoints must be determined on a model-by-model basis. The present work explores the rTg4510 mouse model of tauopathy as a case study to define best practices for the selection and validation of cognitive and functional endpoints for the purposes of pre-clinical AD drug discovery. METHODS: Male rTg4510 mice were first tested at an advanced age, 12 months, in multiple behavioural assays (step 1). Severe tau pathology and neurodegeneration was associated with profound locomotor hyperactivity and spatial memory deficits. Four of these assays were then selected for longitudinal assessment, from 4 to 12 months, to investigate whether behavioural performance changes as a function of accumulation of tau pathology (step 2). Experimental suppression of tau pathology-via doxycycline administration-was also investigated for its effect on functional performance. RESULTS: Progressive behavioural changes were detected where locomotor activity and rewarded alternation were found to most closely correlate with tau burden and neurodegeneration. Doxycycline initiated at 4 months led to a 50% suppression of transgene expression, which was sufficient to prevent subsequent increases in tau pathology and arrest related functional decline. CONCLUSIONS: This two-step approach demonstrates the importance of selecting assays most sensitive to the phenotype of the model. A robust relationship was observed between pathological progression, development of phenotype, and their experimental manipulation-three crucial factors for assessing the translational relevance of future pre-clinical findings.

Persistent gating deficit and increased sensitivity to NMDA receptor antagonism after puberty in a new mouse model of the human 22q11.2 microdeletion syndrome: a study in male mice.

BACKGROUND: The hemizygous 22q11.2 microdeletion is a common copy number variant in humans. The deletion confers high risk for neurodevelopmental disorders, including autism and schizophrenia. Up to 41% of deletion carriers experience psychotic symptoms. METHODS: We present a new mouse model (Df(h22q11)/+) of the deletion syndrome (22q11.2DS) and report on, to our knowledge, the most comprehensive study undertaken to date in 22q11.2DS models. The study was conducted in male mice. RESULTS: We found elevated postpubertal N-methyl-D-aspartate (NMDA) receptor antagonist-induced hyperlocomotion, age-independent prepulse inhibition (PPI) deficits and increased acoustic startle response (ASR). The PPI deficit and increased ASR were resistant to antipsychotic treatment. The PPI deficit was not a consequence of impaired hearing measured by auditory brain stem responses. The Df(h22q11)/+ mice also displayed increased amplitude of loudness-dependent auditory evoked potentials. Prefrontal cortex and dorsal striatal elevations of the dopamine metabolite DOPAC and increased dorsal striatal expression of the AMPA receptor subunit GluR1 was found. The Df(h22q11)/+ mice did not deviate from wild-type mice in a wide range of other behavioural and biochemical assays. LIMITATIONS: The 22q11.2 microdeletion has incomplete penetrance in humans, and the severity of disease depends on the complete genetic makeup in concert with environmental factors. In order to obtain more marked phenotypes reflecting the severe conditions related to 22q11.2DS it is suggested to expose the Df(h22q11)/+ mice to environmental stressors that may unmask latent psychopathology. CONCLUSION: The Df(h22q11)/+ model will be a valuable tool for increasing our understanding of the etiology of schizophrenia and other psychiatric disorders associated with the 22q11DS.

Roles of Hippocampal Somatostatin Receptor Subtypes in Stress Response and Emotionality.

Altered brain somatostatin functions recently appeared as key elements for the pathogenesis of stress-related neuropsychiatric disorders. The hippocampus exerts an inhibitory feedback on stress but the mechanisms involved remain unclear. We investigated herein the role of hippocampal somatostatin receptor subtypes in both stress response and behavioral emotionality using C57BL/6, wild type and sst2 or sst4 knockout mice. Inhibitory effects of hippocampal infusions of somatostatin agonists on stress-induced hypothalamo-pituitary-adrenal axis (HPA) activity were tested by monitoring peripheral blood and local hippocampus corticosterone levels, the latter by using microdialysis. Anxiolytic and antidepressant-like effects were determined in the elevated-plus maze, open field, forced swimming, and stress-sensitive beam walking tests. Hippocampal injections of somatostatin analogs and sst2 or sst4, but not sst1 or sst3 receptor agonists produced rapid and sustained inhibition of HPA axis. sst2 agonists selectively produced anxiolytic-like behaviors whereas both sst2 and sst4 agonists had antidepressant-like effects. Consistent with these findings, high corticosterone levels and anxiety were found in sst2KO mice and depressive-like behaviors observed in both sst2KO and sst4KO strains. Both hippocampal sst2 and sst4 receptors selectively inhibit stress-induced HPA axis activation but mediate anxiolytic and antidepressive effects through distinct mechanisms. Such results are to be accounted for in development of pathway-specific somatostatin receptor agents in the treatment of hypercortisolism (Cushing's disease) and stress-related neuropsychiatric disorders.

Assessing the Cognitive Translational Potential of a Mouse Model of the 22q11.2 Microdeletion Syndrome.

A chromosomal microdeletion at the 22q11.2 locus is associated with extensive cognitive impairments, schizophrenia and other psychopathology in humans. Previous reports indicate that mouse models of the 22q11.2 microdeletion syndrome (22q11.2DS) may model the genetic basis of cognitive deficits relevant for neuropsychiatric disorders such as schizophrenia. To assess the models usefulness for drug discovery, a novel mouse (Df(h22q11)/+) was assessed in an extensive battery of cognitive assays by partners within the NEWMEDS collaboration (Innovative Medicines Initiative Grant Agreement No. 115008). This battery included classic and touchscreen-based paradigms with recognized sensitivity and multiple attempts at reproducing previously published findings in 22q11.2DS mouse models. This work represents one of the most comprehensive reports of cognitive functioning in a transgenic animal model. In accordance with previous reports, there were non-significant trends or marginal impairment in some tasks. However, the Df(h22q11)/+ mouse did not show comprehensive deficits; no robust impairment was observed following more than 17 experiments and 14 behavioral paradigms. Thus - within the current protocols - the 22q11.2DS mouse model fails to mimic the cognitive alterations observed in human 22q11.2 deletion carriers. We suggest that the 22q11.2DS model may induce liability for cognitive dysfunction with additional "hits" being required for phenotypic expression.

Dissociation of mGlu2/3 agonist effects on ketamine-induced regional and event-related oxygen signals.

RATIONALE: Validating preclinical biomarkers that predict treatment efficacy remains a critical imperative for neuropsychiatric drug discovery. With the establishment of novel in vivo imaging methods, it has become possible to think how such translational proof-of-concept studies may look. OBJECTIVES: The aim of this study was to use in vivo oxygen (O2) amperometry to simultaneously assess the regional and event/task-related O2 changes induced by ketamine challenge in rats, and to determine whether both of these signals are equivalently affected by the mGlu2/3 receptor agonist LY379268. METHODS: O2 signals were measured via carbon paste electrodes implanted in the anterior cingulate cortex (ACC) of rats trained to perform a simple reaction time task (SRT). SRT performance, event-related ACC O2 responses, and regional ACC O2 signal were recorded simultaneously in animals treated with ketamine (10 mg/kg) and/or LY379268 (3 mg/kg). RESULTS: A consistent relationship was observed between baseline SRT performance and related ACC O2 signals, suggesting that ACC engagement is likely to be a requirement for optimal task performance. Ketamine induced a robust and consistent slowing in reaction times that was reflected by a delayed event-related ACC O2 signal increase compared to vehicle controls. Ketamine also produced a regional and task-independent 60-min increase in ACC O2 levels which was effectively attenuated by LY379268. However, LY379238 failed to reverse alterations in event-related O2 signals and associated SRT task performance. CONCLUSIONS: These findings raise questions about the degree to which such reversals of regional ketamine O2 signals could potentially be claimed to predict drug treatment efficacy.

Alterations in spatial memory and anxiety in the MAM E17 rat model of hippocampal pathology in schizophrenia.

Adult rats exposed to methylazoxymethanol acetate (MAM) at embryonic day 17 (E17) display robust pathological alterations in the hippocampus. However, discrepancies exist in the literature regarding the behavioural effects of this pre-natal manipulation. Therefore, a systematic assessment of MAM E17-induced behavioural alterations was conducted using a battery of dorsal and ventral hippocampus-dependent tests. Compared to saline controls, MAM E17-treated rats displayed deficits in spatial reference memory in both the aversive hidden platform watermaze task and an appetitive Y-maze task. Deficits in the spatial reference memory watermaze task were replicated across three different cohorts and two laboratories. In contrast, there was little, or no, effect on the non-spatial, visible platform watermaze task or an appetitive, non-spatial, visual discrimination task, respectively. MAM rats were also impaired in the spatial novelty preference task which assesses short-term memory, and displayed reduced anxiety levels in the elevated plus maze task. Thus, MAM E17 administration resulted in abnormal spatial information processing and reduced anxiety in a number of hippocampus-dependent behavioural tests, paralleling the effects of dorsal and ventral hippocampal lesions, respectively. These findings corroborate recent pathological and physiological studies, further highlighting the usefulness of MAM E17 as a model of hippocampal dysfunction in at least some aspects of schizophrenia.

Using Intermediate Cognitive Endpoints to Facilitate Translational Research in Psychosis.

Recent advances in the understanding of psychosis have uncovered potential for a paradigm shift in related drug discovery efforts. The study of psychosis is evolving from its origins in serendipity and empiricism to more formal, hypothesis driven accounts of the cognitive substrates underlying hallucinations and delusions. Recent evidence suggests that misattribution of salience and abnormal prediction error might underlie some forms of psychosis. If substantiated, such intermediate constructs could significantly facilitate translational research for drug discovery. Aberrant salience and prediction error can be assayed with simple tests of associative learning in both species, and a convincing back translation of effects, when combined with measures of neurotransmitter release and brain activity could for the first time allow robust, causal connections to be made between molecular mechanisms in rodents and symptoms in patients.

Temporally distinct cognitive effects following acute administration of ketamine and phencyclidine in the rat.

Non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonists such as phencyclidine (PCP) and ketamine are commonly and interchangeably used to model aspects of schizophrenia in animals. We compared here the effects of acute administration of these compounds over a range of pre-treatment times in tests of instrumental responding (VI 30s response schedule), simple reaction time (SRT) and cognitive flexibility (reversal learning and attentional set shifting digging task) in rats. At standard pre-treatment times (15-30 min), both ketamine and PCP produced overall response suppression in VI 30 and increased reaction times in SRT suggesting that any concomitant cognitive performance deficits are likely to be confounded by motor and/or motivational changes. However, the use of extended pre-treatment times produced deficits in cognitive flexibility measured up to 4h after drug administration in the absence of motor/motivational impairment. Generally, PCP increased impulsive responding in the SRT indicating a possible loss of inhibitory response control that may have contributed to deficits observed in reversal learning and attentional set-shifting. In contrast to PCP, ketamine did not have the same effect on impulsive responding, and possibly as a consequence produced more subtle cognitive deficits in attentional set-shifting. In summary, acute treatment with NMDAR antagonists can produce cognitive deficits in rodents that are relevant to schizophrenia, provided that motor and/or motivational effects are allowed to dissipate. The use of longer pre-treatment times than commonly employed might be advantageous. Also, ketamine, which is more frequently used in clinical settings, did not produce as extensive cognitive deficits as PCP.

The mGlu5 positive allosteric modulator LSN2463359 differentially modulates motor, instrumental and cognitive effects of NMDA receptor antagonists in the rat.

Metabotropic glutamate 5 (mGlu5) receptors are known to functionally interact with N-methyl-d-aspartate (NMDA) receptors at both neuronal and behavioural levels, in a manner that may be of relevance to the treatment of schizophrenia. We have previously described a novel mGlu5 positive allosteric modulator (PAM), LSN2463359 and provided evidence of its ability to attenuate aspects of the behavioural response to administration of the competitive NMDA receptor antagonist, SDZ 220,581. In addition, LSN2463359 was found to selectively attenuate reversal learning deficits observed in the neurodevelopmental MAM E17 model but not in the acute phencyclidine (PCP) model. In the present study, the interactions between this mGlu5 PAM and the NMDA receptor were explored further by assessing the effects of LSN2463359 against some of the motor, instrumental and cognitive effects induced by the non-competitive NMDA receptor antagonists PCP and MK-801, the competitive NMDA receptor antagonist SDZ 220,581 and the GluN2B selective NMDA receptor antagonist, Ro 63-1908. LSN2463359 had either no or minor impact on locomotor hyperactivity induced by either PCP or SDZ 220,581. However, in rats lever pressing for food rewards under a variable interval 30s schedule of instrumental responding, the drug clearly attenuated not only the suppression of response rate induced by SDZ 220,581 but also the stimulation of response rate induced by Ro 63-1908. In contrast, LSN2463359 failed to alter both of the instrumental effects induced by the open channel blockers PCP and MK-801. In addition, although PCP and SDZ 220,581 induced similar deficits in a discrimination and reversal learning task, LSN2463359 was again only able to reverse the deficit induced by SDZ 220,581. The results indicate that the interactions between mGlu5 and NMDA receptors are dependent on both the mechanism of the blockade of the receptor and the behavioural domain under investigation. Our work has implications for the preclinical use of NMDA receptor antagonists in the prediction of potential therapeutic efficacy in the search for novel treatments for schizophrenia. Positive allosteric modulators of the mGlu5 receptor certainly question the predictive validity of such approaches. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

In vitro characterisation of the novel positive allosteric modulators of the mGlu5 receptor, LSN2463359 and LSN2814617, and their effects on sleep architecture and operant responding in the rat.

The demonstrated functional interaction of metabotropic glutamate 5 (mGlu5) receptors with N-methyl-d-aspartate (NMDA) receptors has prompted speculation that their activation may offer a potential treatment for aspects of schizophrenia. Development of selective mGlu5 agonists has been difficult, but several different positive allosteric modulator (PAM) molecules have now been identified. This study describes two novel mGlu5 PAMs, LSN2463359 (N-(1-methylethyl)-5-(pyridin-4-ylethynyl)pyridine-2-carboxamide) and LSN2814617 [(7S)-3-tert-butyl-7-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-A]pyridine], which are useful tools for this field of research. Both compounds are potent and selective potentiators of human and rat mGlu5 receptors in vitro, displaying curve shift ratios of two to three fold in the concentration-response relationship to glutamate or the glutamate receptor agonist, DHPG, with no detectable intrinsic agonist properties. Both compounds displaced the mGlu5 receptor antagonist radioligand, [³H]MPEP in vitro and, following oral administration reached brain concentrations sufficient to occupy hippocampal mGlu5 receptors as measured in vivo by dose-dependent displacement from the hippocampus of intravenously administered MPEPy. In vivo EEG studies demonstrated that these mGlu5 PAMs have marked wake-promoting properties but little in the way of rebound hypersomnolence. In contrast, the previously described mGlu5 PAMs CDPPB and ADX47273 showed relatively poor evidence of in vivo target engagement in either receptor occupancy assays or EEG disturbance. Wake-promoting doses of LSN2463359 and LSN2814617 attenuated deficits in performance induced by the competitive NMDA receptor antagonist SDZ 220,581 in two tests of operant behaviour: the variable interval 30 s task and the DMTP task. These effects were lost if the dose of either compound extended into the range which disrupted performance in the baseline DMTP task. However, the improvements in response accuracy induced by the mGlu5 potentiators in SDZ 220,581-treated rats were not delay-dependent and, therefore, perhaps more likely reflected optimization of general arousal than specific beneficial effects on discrete cognitive processes. The systematic profiling of LSN2463359 and LSN2814617 alongside other previously described molecules will help determine more precisely how mGlu5 potentiator pharmacology might provide therapeutic benefit. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

NMDA receptors, cognition and schizophrenia--testing the validity of the NMDA receptor hypofunction hypothesis.

Cognitive dysfunction is core to schizophrenia, and remains poorly treated by existing therapies. A prominent hypothesis suggests that many symptoms arise from N-methyl-d-aspartate receptor (NMDAR) hypofunction. Subsequently, there has emerged a widespread use of many preclinical and clinical NMDAR antagonist models in the search for novel treatments. Clinically, ketamine is broadly purported to induce cognitive symptoms similar to those of schizophrenia. Preclinically, acute, subchronic and neonatal NMDAR antagonist administration models are all utilised in this context, as well as NMDAR transgenic animals. In this review, key strengths and weaknesses of each of these approaches are described with regard to their ability to recapitulate the deficits seen in patients. Given the breadth of literature and vogue for research in this topic, instances of NMDAR antagonist effects in the desired domains can readily be found preclinically. However, it is surprisingly difficult to identify any single aspect of cognitive function that possesses complete translational integrity. That is, there does not seem to be an NMDAR antagonist regimen proven to engage NMDARs equivalently in humans and animals that reliably produces the same cognitive effects in each species. This is likely due to the diverse range of techniques and models used by preclinical researchers, a paucity of research describing pharmacokinetic-pharmacodynamic relationships of NMDAR antagonist regimens, little capability to measure target engagement, and the lack of harmonized procedures between preclinical and clinical studies. Realizing the potential of the NMDAR hypofunction hypothesis to model cognitive impairment in schizophrenia will require some of these issues to be addressed.

Selective remediation of reversal learning deficits in the neurodevelopmental MAM model of schizophrenia by a novel mGlu5 positive allosteric modulator.

Based on the glutamatergic hypothesis of schizophrenia we assessed the effects of a novel mGlu5 positive allosteric modulator, LSN2463359 [N-(1-methylethyl)-5-(pyridin-4-ylethynyl)pyridine-2-carboxamide] on deficits in cognitive flexibility in two distinct rodent models of schizophrenia, the neurodevelopmental MAM E17 model and the acute PCP model. Cognitive flexibility was measured with the intra-dimensional and extra-dimensional set-shifting and reversal learning digging paradigm. Regional effects of MAM on the expression of parvalbumin-positive cells (PV) and mGlu5 receptors were also examined, to further characterize the model. Results showed that LSN2463359 selectively attenuated reversal learning deficits in the MAM but not acute PCP model. Whilst both models led to deficits in reversal learning and extra-dimensional set-shifting, the reversal impairments were qualitatively distinct, with MAM increasing perseverative responding, whereas the PCP deficit was mainly due to the inability of rats to maintain reinforced choice behavior. Reduction of PV and mGlu5 expression was found in the MAM model in several regions of importance in schizophrenia, such as the orbitofrontal and medial prefrontal cortex, which also mediate reversal learning and extra-dimensional set-shifting. The present findings confirm that the positive modulation of mGlu5 receptors may have beneficial effects in the treatment of certain aspects of cognitive impairment associated with schizophrenia. This study also illustrates the importance of studying putative cognitive enhancing drug effects in a number of models which may have implications for the future development of the compound.

A comparison of the effects of ketamine and phencyclidine with other antagonists of the NMDA receptor in rodent assays of attention and working memory.

RATIONALE: N-methyl-D: -Aspartate receptor (NMDAR) antagonists such as ketamine induce cognitive symptoms in man similar to those of schizophrenia and therefore might be useful as models of the disease in animals. However, it is unclear which NMDAR antagonist(s) offer the best means to produce cognitive deficits in attention and working memory and to what extent those deficits can be measured selectively in rats. OBJECTIVES: The present study systematically compared the effects of eight different NMDAR antagonists-MK-801, phencyclidine, (S)-(+)-ketamine, memantine, SDZ-220,581, Ro 25-6981, CP 101-606 and NVP-AAM077-in rats using standard tests of visual attention, the five-choice serial reaction time task (5CSRT), and working memory, the delayed matching to position task (DMTP). RESULTS: Drug-induced responses varied qualitatively and quantitatively in both a compound- and a task-dependent manner. Effects were generally confounded by concomitant motor and motivational disruption, although individual doses of phencyclidine for example appeared to impair selectively cognitive functions. Interestingly, GluN2B selective antagonists were unique in their effects; inducing potential performance benefit in the 5CSRT. CONCLUSIONS: Overall, the opportunity to induce a selective cognitive deficit in attention (5CSRT) or working memory (DMTP) in the rat is limited by both the NMDAR antagonist and the dose range used. The importance of a preclinical focus on ketamine, which is used more frequently in clinical settings, is limited by the extent to which cognitive effects can be both detected and quantified using this exposure regimen within these two operant assays.

Cooperation between hippocampal somatostatin receptor subtypes 4 and 2: functional relevance in interactive memory systems.

The hippocampal somatostatin (sst) receptor subtype 4 (sst(4)) modulates memory formation by diminishing hippocampus-based spatial function while enhancing striatum-dependent behaviors. sst(4)-mediated regulations on neuronal activity in the hippocampus appear to depend on both competitive and cooperative interactions with sst receptor subtype 2 (sst(2)). Here, we investigated whether interactions with sst(2) receptors are required for sst(4)-mediated effects on hippocampus-dependent spatial memory and striatum-dependent cued memory in a water maze paradigm. Competition was assessed in mice by intrahippocampal injections of the sst(4) agonist L-803,087 alone or combined with sst(2) agonists (L-779,976 or octreotide). Effects of L-803,087 were also tested in sst(2) knockout mice to assess for receptor cooperation. Finally, sst(2a) and sst(4) localizations within hippocampal subregions were analyzed by immunohistochemistry and expression levels of sst(2a) and sst(2b) were quantified by real-time qPCR. Hippocampal injections of L-803,087 impaired spatial memory but enhanced cued memory. The latter effect was lost not only in sst(2) knockout mice but also in the presence of sst(2) agonists, whereas the former effect remained unaffected by sst(2) agonists or gene deletion. Octreotide and L-779,976 did not yield memory effects but reduced swim velocity throughout the acquisition trials suggesting that stimulation of sst(2) affected motivation and/or anxiety. sst(2a) and sst(4) were respectively detected in the dentate gyrus (DG) and the CA1 subfield suggesting that their functional interactions are not mediated by direct receptor coupling. Hippocampus sst(2a) expression was 36-fold higher than sst(2b). Possible neural mechanisms and functional significances for interaction between memory systems in relationship with stress-induced changes in hippocampal functions are discussed.

Somatostatin, Alzheimer's disease and cognition: an old story coming of age?

In mammalian brain, the somatostatin (SRIF: somatotropin release-inhibiting factor) family is composed of two peptides: SRIF and cortistatin (CST), which interact with five different receptor subtypes, sst(1-5). This review summarizes the properties of these receptors, the involvement of somatostatinergic systems in Alzheimer's disease (SRIF/acetylcholine (Ach), SRIF/amyloid beta peptides, and SRIF/tau interactions) and their role in cognition from early studies using cysteamine as an SRIF depleting substance to the use of subtype selective analogues and knockout mice, and modulation of synaptic plasticity. The current SRIF story illustrates how cognition and emotion are intimately integrated in brain function.

Hippocampal SSTR4 somatostatin receptors control the selection of memory strategies.

RATIONALE: Somatostatin (SS14) has been implicated in various cognitive disorders, and converging evidence from animal studies suggests that SS14 neurons differentially regulate hippocampal- and striatal-dependent memory formation. Four SS14 receptor subtypes (SSTR1-4) are expressed in the hippocampus, but their respective roles in memory processes remain to be determined. OBJECTIVES: In the present study, effects of selective SSTR1-4 agonists on memory formation were assessed in a water-maze task which can engage either hippocampus-dependent "place" and/or striatum-dependent "cue" memory formation. MATERIALS AND METHODS: Mice received an intrahippocampal injection of one of each of the selective agonists and were then trained to locate an escape platform based on either distal cues (place memory) or a visible proximal cue (cue memory). Retention was tested 24 h later on probe trials aimed at identifying which memory strategy was preferentially retained. RESULTS: Both SS14 and the SSTR4 agonist (L-803,087) dramatically impaired place memory formation in a dose-dependent manner, whereas SSTR1 (L-797,591), SSTR2 (L-779,976), or SSTR3 (L-796,778) agonists did not yield any behavioral effects. However, unlike SS14, the SSTR4 agonist also dose-dependently enhanced cue-based memory formation. This effect was confirmed in another striatal-dependent memory task, the bar-pressing task, where L-803,087 improved memory of the instrumental response, whereas SS14 was once again ineffective. CONCLUSIONS: These data suggest that hippocampal SSTR4 are selectively involved in the selection of memory strategies by switching from the use of hippocampus-based multiple associations to the use of simple dorsal striatum-based behavioral responses. Possible neural mechanisms and functional implications are discussed.