Transient overexpression of the 5-HT1A receptor impairs water-maze but not hole-board performance

Previously, we showed that mice that overexpress the 5-HT(1A) receptor transiently from embryonic to perinatal stages show reduced anxiety and changes in brain serotonin turnover as adults. Here, we investigated the long-term effects of the temporary overexpression of the 5-HT(1A) receptor during early embryonic and perinatal development on the performance in two memory tasks. In the hole-board test mice that were homozygous for the transgene showed similar behavioral habituation but increased locomotion compared to heterozygous mice. In contrast water-maze performance of homozygous mice was impaired compared to heterozygous mice. These results suggest that a transient overexpression of 5-HT(1A) receptor during embryonic and perinatal development has detrimental effects on water-maze performance at adult stages.     

Two novel 5-HT6 receptor antagonists ameliorate scopolamine-induced memory deficits in the object recognition and object location tasks in Wistar rats

The 5-hydroxytryptamine₆ (5-HT₆) receptor has been suggested to play an important role in the regulation of memory and cognition. In the present study, our aim was to investigate whether the novel, selective 5-HT₆ antagonists compound (CMP) X and CMP Y and the reference 5-HT₆ antagonist GSK-742457 could ameliorate impairments in episodic memory in 3-months-old male Wistar rats. The acetylcholinesterase inhibitor (AChEI) donepezil (Aricept®, approved for symptomatic treatment of Alzheimer’s disease, AD) was used as a positive reference compound. First, effects of the 5-HT₆ antagonists CMP X, CMP Y and GSK-742457 were investigated on object recognition task (ORT) performance in rats treated with the muscarinic antagonist scopolamine (0.1 mg/kg, administered intraperitoneally, i.p., 30 min before trial 1). Second, effects of the combination of suboptimal doses of 5-HT₆ antagonists CMP X and CMP Y with the AChEI donepezil were studied, to determine whether the 5-HT₆ antagonists show additive synergism with donepezil in the ORT. Finally, effects of CMP Y, GSK-742457 and donepezil were investigated on object location task (OLT) performance in rats treated with scopolamine.Donepezil (1 mg/kg, oral administration, p.o.), GSK-742457 (3 mg/kg, i.p.), CMP X (3 mg/kg, i.p.) and CMP Y (30 mg/kg, p.o.), all ameliorated the scopolamine-induced deficits in object recognition. In the ORT, we have found that combined administration of subthreshold doses of CMP X (1 mg/kg, i.p.) and CMP Y (10 mg/kg, p.o.) with the AChEI donepezil (0.1 mg/kg, p.o.), enhanced memory performance in Wistar rats with deficits induced by scopolamine. Donepezil (0.1 mg/kg, p.o.) alone had no discernable effects on performance. This suggests additive synergistic effects of the 5-HT₆ antagonists (CMP X and CMP Y) with donepezil on cognitive impairment. Finally, donepezil (1 mg/kg, p.o.), GSK-742457 (10 mg/kg, p.o.) and CMP Y (30 mg/kg, p.o.) also reduced scopolamine-induced deficits in the OLT.In conclusion, the 5-HT₆ antagonists were found to clearly improve episodic memory deficits induced by scopolamine. In addition, co-administration of the 5-HT₆ receptor antagonists CMP X and CMP Y with the AChEI donepezil to cognitively impaired rats also resulted in potentially additive enhancing effects on cognition. This suggests that these compounds could have potential as monotherapy, but also as adjunctive therapy in patients with AD treated with common treatments such as donepezil.     

Aggression is suppressed by acute stress but induced by chronic stress: Immobilization effects on aggression, hormones, and cortical 5-HT1B/ striatal dopamine D2 receptor density

Although it has been established by a number of investigators that a variety of stressors are associated with the induction of aggressive behavior, two specific issues remain unanswered. First, it is unclear whether the contexts surrounding stressors (e.g., stressor length and chance of winning over opponents) change outcomes regarding aggressive behavior. Second, if a relationship exists between stress and aggressive behavior, altered levels of stress-related hormone (e.g., corticosterone [CORT]), as well as aggression-related biomarkers (e.g., testosterone [T], density of prefronto-cortical 5-HT(1B) receptor and striatal dopamine D(2) receptor [D2r]) may contribute to changes in aggressive behavior. Thus, we examined how immobilization (with a 1-, 5-, or 10-day exposure) would impact (1) a longitudinal course of aggression toward different-sized opponents, (2) levels of CORT and T, and (3) densities of 5-HT(1B) receptor (5-HT1Br) in the prefrontal cortex (PFC) and D2r in the striatum. It was found that, regardless of small or large opponents, a single 2-h exposure to immobilization reduced aggressive behavior (stress-suppressed aggression) over time, whereas repeated (10-day) exposure to immobilization escalated aggressive behavior (stress-induced aggression). These stress effects persisted up to 1 week of recovery from immobilization stress. Moreover, immobilized rats demonstrated elevated levels of T, but not CORT, as compared with controls. Finally, acute immobilization altered D2r densities in the shell of the nucleus accumbens, and chronic immobilization changed 5-HT1Br in the PFC, including the downregulation of 5-HT1Br densities in the right prelimbic and orbitolateral cortices. The potential relationships among stress, aggression, and 5-HT1Br/D2r roles are discussed.     

Rapid visual learning in the rat: Effects at the 5-HT 1a receptor subtype

The 5-hydroxytryptamine 1a (5-HT 1a ) receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT; 0.15 mg/kg) impaired rats' rapid visual learning on a computerized maze. This treatment also increased decision time (DT) but the learning impairment was not necessarily a side-effect of slower responding because, in this task, responses made at long DT are more accurate than those at short DT. The selective 5-HT 1a receptor antagonist WAY-100635 (0.3 mg/kg) was itself without effect on accuracy, but was effective in reversing effects of 8-OH-DPAT (on both accuracy and DT). Within problems (i.e., over the 40-60 trials of a single discrimination), performance was reduced by treatment with 8-OH-DPAT at all stages of learning. We conclude that this effect is mediated through the 5-HT 1a receptor site (rather than through some other serotonergic receptor site or non-specific mechanism) as it was reversible by treatment with WAY-100635. Although it could still arise from behaviourally non-specific effects, the performance deficit finds its best account in terms of the psychological processes necessary to visual learning. Its reversal with WAY-100635 offers support to the hypothesis that 5-HT 1a receptor antagonists could improve cognitive function, under conditions of pre-existing impairment due to overactive serotonergic inhibition, as is thought to occur in Alzheimer's disease.     

A1 is not a conservative extension of S4 but of S5

In [1], D. W. Hart and C. Mcginn considered two logics A1 and A2. These logics embody part of a tradition about a priori knowledge and necessity. They proved that A2 is a conservative extension of a well-known modal logic S5 but left the problem whether A1 is a conservative extension of S4 open. In this note, we shall show that A1 is not a conservative extension of S4 but of S5, and also correct an inadequate proof.     

A pharmacological analysis of an associative learning task: 5-HT(1) to 5-HT(7) receptor subtypes function on a pavlovian/instrumental autoshaped memory

Recent studies using both invertebrates and mammals have revealed that endogenous serotonin (5-hydroxytryptamine [5-HT]) modulates plasticity processes, including learning and memory. However, little is currently known about the mechanisms, loci, or time window of the actions of 5-HT. The aim of this review is to discuss some recent results on the effects of systemic administration of selective agonists and antagonists of 5-HT on associative learning in a Pavlovian/instrumental autoshaping (P/I-A) task in rats. The results indicate that pharmacological manipulation of 5-HT1-7 receptors or 5-HT reuptake sites might modulate memory consolidation, which is consistent with the emerging notion that 5-HT plays a key role in memory formation.     

Depletion of brain serotonin differently affects behaviors induced by 5HT1A, 5HT1C, and 5HT2 receptor activation in rats.

5-hydroxytryptamine (5HT)-depleted rats were subjected to behavioral experiments in which the response to activation of 5HT1A, 5HT1c, and 5HT2 receptor subtypes was measured. Depletion of 5HT was produced by unilateral intracerebroventricular injection of 5,7-dihydroxytryptamine (100 micrograms/rat) or by systemic injection of p-chlorophenylalanine (150 mg/kg injected intraperitoneally 72, 48, and 24 h before the test). The dose-response curve of the 5HT1A-mediated, 8-hydroxy-2-(di-n-propylamino)tetralin (0.022-0.46 mg/kg)-induced lower lip retraction was not changed after depletion, nor was the dose-response curve of the 5HT2 receptor-mediated (+-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (0.046-1.0 mg/kg)-induced head shake response. The dose-response curve for penile erections, a 5HT1c receptor-mediated response after mCPP (0.1-1.0 mg/kg), a direct 5HT1c agonist, is shifted to the left after 5HT depletion, whereas the response to indirect activation of the 5HT1c receptor with the 5HT reuptake inhibitors citalopram (2.2-4.6 mg/kg) and paroxetine (0.22-2.2 mg/kg) was inhibited after 5HT depletion. These results suggest that 5HT1c receptors are more subject to denervation supersensitivity than 5HT1A and 5HT2 receptors. This lesion model may be useful to discriminate behaviorally between direct and indirect activation of the 5HT1c receptor.     

Enhanced retention in the passive-avoidance task by 5-HT(1A) receptor blockade is not associated with increased activity of the central nucleus of the amygdala

The effect of blockade of 5-HT1A receptors was investigated on (1). retention in a mildly aversive passive-avoidance task, and (2). spontaneous single-unit activity of central nucleus of the amygdala (CeA) neurons, a brain site implicated in modulation of retention. Systemic administration of the selective 5-HT1A antagonist NAN-190 immediately after training markedly-and dose-dependently-facilitated retention in the passive-avoidance task; enhanced retention was time-dependent and was not attributable to variations in wattages of shock received by animals. Systemic administration of NAN-190 had mixed effects on spontaneous single-unit activity of CeA neurons recorded extracellularly in vivo; microiontophoretic application of 5-HT, in contrast, consistently and potently suppressed CeA activity. The present findings-that 5-HT1A receptor blockade by NAN-190 (1). enhances retention in the passive-avoidance task, and (2). does not consistently increase spontaneous neuronal activity of the CeA-provide evidence that a serotonergic system tonically inhibits modulation of retention in the passive-avoidance task through activation of the 5-HT1A receptor subtype at brain sites located outside the CeA.     

LTP in hippocampal area CA1 is induced by burst stimulation over a broad frequency range centered around delta

Long-term potentiation (LTP) is typically studied using either continuous high-frequency stimulation or theta burst stimulation. Previous studies emphasized the physiological relevance of theta frequency; however, synchronized hippocampal activity occurs over a broader frequency range. We therefore tested burst stimulation at intervals from 100 msec to 20 sec (10 Hz to 0.05 Hz). LTP at Schaffer collateral–CA1 synapses was obtained at intervals from 100 msec to 5 sec, with maximal LTP at 350–500 msec (2–3 Hz, delta frequency). In addition, a short-duration potentiation was present over the entire range of burst intervals. We found that N-methyl-d-aspartic acid (NMDA) receptors were more important for LTP induction by burst stimulation, but L-type calcium channels were more important for LTP induction by continuous high-frequency stimulation. NMDA receptors were even more critical for short-duration potentiation than they were for LTP. We also compared repeated burst stimulation with a single primed burst. In contrast to results from repeated burst stimulation, primed burst potentiation was greater when a 200-msec interval (theta frequency) was used, and a 500-msec interval was ineffective. Whole-cell recordings of postsynaptic membrane potential during burst stimulation revealed two factors that may determine the interval dependence of LTP. First, excitatory postsynaptic potentials facilitated across bursts at 500-msec intervals but not 200-msec or 1-sec intervals. Second, synaptic inhibition was suppressed by burst stimulation at intervals between 200 msec and 1 sec. Our data show that CA1 synapses are more broadly tuned for potentiation than previously appreciated.Long-term potentiation (LTP) is used as a model for studying synaptic events during learning and memory (Bliss and Collingridge 1993; Morris 2003; Lynch 2004). At most synapses, LTP is triggered by postsynaptic Ca²⁺ influx through N-methyl-d-aspartic acid (NMDA) glutamate receptors (Collingridge et al. 1983; Harris et al. 1984; Herron et al. 1986) and, under some conditions, through L-type voltage-gated Ca²⁺ channels (Grover and Teyler 1990, 1994; Morgan and Teyler 1999). LTP was discovered in the dentate gyrus (Bliss and Lomo 1973) following several seconds of 10–100 Hz stimulation of the perforant path. Since then, many LTP studies have used similar long, high-frequency stimulation (HFS) protocols, most typically 100 Hz, 1 sec (Bliss and Collingridge 1993). Although effective, HFS does not resemble physiological patterns of activity (Albensi et al. 2007). Patterned stimulation resembling physiological activity, in particular theta burst stimulation, is also effective for LTP induction (Larson et al. 1986; Staubli and Lynch 1987; Capocchi et al. 1992; Nguyen and Kandel 1997). Theta burst stimulation consists of short bursts (4–5 stimuli at 100 Hz) repeated at 5 Hz, which lies within the hippocampal theta frequency range (4–12 Hz) (Bland 1986; Buzsáki 2002). Primed burst stimulation, another form of patterned stimulation, involves delivery of a priming stimulus followed by a single short burst (Larson and Lynch 1986; Rose and Dunwiddie 1986). The temporal requirements for primed burst LTP are quite precise (Diamond et al. 1988; Greenstein et al. 1988; Larson and Lynch 1989): Intervals less than 140 msec or greater than 200 msec are ineffective.The mechanisms underlying theta frequency-dependent LTP have been studied primarily using the primed burst protocol (Larson and Lynch 1986, 1988, 1989; Pacelli et al. 1989; Davies and Collingridge 1996). Activation of GABA_B autoreceptors during the priming stimulus suppresses GABA release during the following burst (Davies et al. 1990; Lambert and Wilson 1994; Olpe et al. 1994), allowing greater postsynaptic depolarization (Larson and Lynch 1986; Pacelli et al. 1989) and more effective NMDA receptor activation (Davies and Collingridge 1996). Consequently, temporal requirements for primed burst potentiation match the time course of GABA_B autoreceptor-mediated suppression of GABA release (Davies et al. 1990; Davies and Collingridge 1993; Mott et al. 1993).Besides theta, hippocampal activity is observed at other frequencies, notably sharp waves (0.01–5 Hz) (Buzsáki 1986, 1989; Suzuki and Smith 1987) and low-frequency oscillations (≤1 Hz) (Wolansky et al. 2006; Moroni et al. 2007). These lower frequencies dominate during slow wave sleep (Buzsáki 1986; Suzuki and Smith 1987; Wolansky et al. 2006; Moroni et al. 2007), and contribute to hippocampal memory processing (Buzsáki 1989; Pennartz et al. 2002). While synchronized population activity over frequencies from <1 Hz to 12 Hz is associated with hippocampal memory function, previous LTP studies have focused on theta. We therefore investigated burst stimulation at frequencies from 0.05 Hz to 10 Hz. We found that CA1 synapses potentiate to some degree over this entire range and that maximal potentiation occurs around delta frequency rather than theta.     

Neurochemical regulation of feeding in the rat: facilitation by alpha-noradrenergic, but not dopaminergic, receptor stimulants.

Rats ate voraciously after intraventricular injections of the alpha-noradrenergic receptor stimulant clonidine. Intraventricular administration of l-norepinephrine also facilitated feeding, but similar injections of dopamine and apomorphine (a dopamine receptor stimulant) were ineffective and even tended to suppress feeding. Clonidine was 100 times more potent than norepinephrine and increased the intake of both the ordinary diet of powdered food and a highly palatable wet food. The anorexic action of amphetamine was reversed by centrally administered clonidine. These observations suggest "respondent" rather than "operant" regulation of feeding by noradrenergic systems. That is, in relation to noradrenergic mechanisms, feeding appears to be a respondent which is sensitized or disinhibited by activation of alpha-noradrenergic receptors, rather than an operant which is reinforced by the release of norepinephrine.     

Mitral cell beta1 and 5-HT2A receptor colocalization and cAMP coregulation: a new model of norepinephrine-induced learning in the olfactory bulb

In the present study we assess a new model for classical conditioning of odor preference learning in rat pups. In preference learning beta(1)-adrenoceptors activated by the locus coeruleus mediate the unconditioned stimulus, whereas olfactory nerve input mediates the conditioned stimulus, odor. Serotonin (5-HT) depletion prevents odor learning, with 5-HT(2A/2C) agonists correcting the deficit. Our new model proposes that the interaction of noradrenergic and serotonergic input with odor occurs in the mitral cells of the olfactory bulb through activation of cyclic adenosine monophosphate (cAMP). Here, using selective antibodies and immunofluorescence examined with confocal microscopy, we demonstrate that beta(1)-adrenoceptors and 5-HT(2A) receptors colocalize primarily on mitral cells. Using a cAMP assay and cAMP immunocytochemistry, we find that beta-adrenoceptor activation by isoproterenol, at learning-effective and higher doses, significantly increases bulbar cAMP, as does stroking. As predicted by our model, the cAMP increases are localized to mitral cells. 5-HT depletion of the olfactory bulb does not affect basal levels of cAMP but prevents isoproterenol-induced cAMP elevation. These results support the model. We suggest the mitral-cell cAMP cascade converges with a Ca(2+) pathway activated by odor to recruit CREB phosphorylation and memory-associated changes in the olfactory bulb. The dose-related increase in cAMP with isoproterenol implies a critical cAMP window because the highest dose of isoproterenol does not produce learning.     

Spatial learning in the 5-HT1B receptor knockout mouse: selective facilitation/impairment depending on the cognitive demand

Age-related memory decline is associated with a combined dysfunction of the cholinergic and serotonergic systems in the hippocampus and frontal cortex, in particular. The 5-HT1B receptor occupies strategic cellular and subcellular locations in these structures, where it plays a role in the modulation of ACh release. In an attempt to characterize the contribution of this receptor to memory functions, 5-HT1B receptor knockout (KO) mice were submitted to various behavioral paradigms carried out in the same experimental context (water maze), which were aimed at exposing mice to various levels of memory demand. 5-HT1BKO mice exhibited a facilitation in the acquisition of a hippocampal-dependent spatial reference memory task in the Morris water maze. This facilitation was selective of task difficulty, showing thus that the genetic inactivation of the 5-HT1B receptor is associated with facilitation when the complexity of the task is increased, and reveals a protective effect on age-related hippocampal-dependent memory decline. Young-adult and aged KO and wild-type (WT) mice were equally able to learn a delayed spatial matching-to-sample working memory task in a radial-arm water maze with short (0 or 5 min) delays. However, 5-HT1BKO mice, only, exhibited a selective memory impairment at intermediate and long (15, 30, and 60 min) delays. Treatment by scopolamine induced the same pattern of performance in wild type as did the mutation for short (5 min, no impairment) and long (60 min, impairment) delays. Taken together, these studies revealed a beneficial effect of the mutation on the acquisition of a spatial reference memory task, but a deleterious effect on a working memory task for long delays. This 5-HT1BKO mouse story highlights the problem of the potential existence of "global memory enhancers."     

Agency affects adults', but not children's,guessing preferences in a game of chance

Adults and children have recently been shown to prefer guessing the outcome of a die roll after the die has been rolled (but remained out of sight) rather than before it has been rolled. This result is contrary to the predictions of the competence hypothesis (Heath & Tversky, 1991 Heath, C. and Tversky, A. 1991. PREFerence and belief: Ambiguity and competence in choice under uncertainty. Journal of Risk and Uncertainty, 4: 5–28. [Crossref], [Web of Science ®] , [Google Scholar]), which proposes that people are sensitive to the degree of their relative ignorance and therefore prefer to guess about an outcome it is impossible to know, rather than one that they could know, but do not. We investigated the potential role of agency in guessing preferences about a novel game of chance. When the experimenter controlled the outcome, we replicated the finding that adults and 5- to 6-year-old children preferred to make their guess after the outcome had been determined. For adults only, this preference reversed when they exerted control over the outcome about which they were guessing. The adult data appear best explained by a modified version of the competence hypothesis that highlights the notion of control or responsibility. It is proposed that potential attributions of blame are related to the guesser's role in determining the outcome. The child data were consistent with an imagination-based account of guessing preferences.     

Agency affects adults', but not children's, guessing preferences in a game of chance

Adults and children have recently been shown to prefer guessing the outcome of a die roll after the die has been rolled (but remained out of sight) rather than before it has been rolled. This result is contrary to the predictions of the competence hypothesis (Heath & Tversky, 1991 ), which proposes that people are sensitive to the degree of their relative ignorance and therefore prefer to guess about an outcome it is impossible to know, rather than one that they could know, but do not. We investigated the potential role of agency in guessing preferences about a novel game of chance. When the experimenter controlled the outcome, we replicated the finding that adults and 5- to 6-year-old children preferred to make their guess after the outcome had been determined. For adults only, this preference reversed when they exerted control over the outcome about which they were guessing. The adult data appear best explained by a modified version of the competence hypothesis that highlights the notion of control or responsibility. It is proposed that potential attributions of blame are related to the guesser's role in determining the outcome. The child data were consistent with an imagination-based account of guessing preferences.     

Amygdala upregulation of NCAM polysialylation induced by auditory fear conditioning is not required for memory formation, but plays a role in fear extinction

There is much interest to understand the mechanisms leading to the establishment, maintenance, and extinction of fear memories. The amygdala has been critically involved in the processing of fear memories and a number of molecular changes have been implicated in this brain region in relation to fear learning. Although neural cell adhesion molecules (NCAMs) have been hypothesized to play a role, information available about their contribution to fear memories is scarce. We investigate here whether polysialylated NCAM (PSA-NCAM) contributes to auditory fear conditioning in the amygdala. First, PSA-NCAM expression was evaluated in different amygdala nuclei after auditory fear conditioning at two different shock intensities. Results showed that PSA-NCAM expression was increased 24 h post-training only in animals subjected to the highest shock intensity (1mA). Second, PSA-NCAM was cleaved in the basolateral amygdaloid complex through micro-infusions of the enzyme endoneuraminidase N, and the consequences of such treatment were investigated on the acquisition, consolidation, remote memory expression, and extinction of conditioned fear memories. Intra-amygdaloid cleavage of PSA-NCAM did not affect acquisition, consolidation or expression of remote fear memories. However, intra-amygdaloid PSA-NCAM cleavage enhanced fear extinction processes. These results suggest that upregulation of PSA-NCAM is a correlate of fear conditioning that is not necessary for the establishment of fear memory in the amygdala, but participates in mechanisms precluding fear extinction. These findings point out PSA-NCAM as a potential target for the treatment of psychopathologies that involve impairment in fear extinction.     

Microinfusion of the D1 receptor antagonist, SCH23390 into the IL but not the BLA impairs consolidation of extinction of auditory fear conditioning

In auditory fear conditioning, repeated presentation of the tone in the absence of the shock leads to extinction of the acquired fear response. Both the medial prefrontal cortex (mPFC) and the basolateral amygdala (BLA) are involved in extinction. Here we examined this involvement by antagonizing D1 receptors in both regions, in the rat. We microinfused the D1 receptor antagonist, SCH23390, into the infra-limbic part of the mPFC (IL) or BLA at different time points. SCH23390 mircoinfused into the IL either before extinction acquisition or following short extinction training resulted in impairment of extinction consolidation. Microinfusion of SCH23390 into the BLA, prior to acquisition of extinction caused impairment in acquisition of extinction without affecting extinction consolidation. This is supported by the results showing that microinfusion of SCH23390 into the BLA following a short-training session did not affect consolidation. These results further strengthen the role of mPFC in consolidation of extinction while highlighting the role of the D1 receptors in this process.     

Exploitation of pointing as a referential gesture in young children, but not adolescent chimpanzees

The ability of adolescent chimpanzees and 2- and 3-year-old children to use pointing gestures to locate hidden surprises was examined in two experiments. The results revealed that although young 2-year-old children appeared to have no difficulty extracting referential information from a pointing gesture (independent of gaze or distance cues) and spontaneously using it to search in specific locations, adolescent chimpanzees appeared to rely on cueconfiguration and distance-based rules. Thus, although these chimpanzees were trained to respond appropriately to the pointing gestures of a human by searching in a particular location, this ability did not easily generalize to situations in which the distance between the pointing hand and the location were more distal. Furthermore, even those chimpanzees that were able to generalize in this fashion appeared to use distance-based cues, not ones based on an appreciation of the internal attentional focus or mental referent of the experimenter as indicated by his pointing gesture.     

Delay-dependent working memory impairment in young-adult and aged 5-HT1BKO mice as assessed in a radial-arm water maze

Serotonin (5-HT) plays a modulatory role in mnemonic functions, especially by interacting with the cholinergic system. The 5-HT1B receptor is a key target of this interaction. The 5-HT1B receptor knockout mice were found previously to exhibit a facilitation in hippocampal-dependent spatial reference memory learning. In the present study, we submitted mice to a delayed spatial working memory task, allowing the introduction of various delays between an exposure trial and a test trial. The 5-HT1BKO and wild-type mice learned the task in a radial-arm water maze (returning to the most recent presented arm containing the escape platform), and exhibited a high level of performance at delays of 0 and 5 min. However, at the delay of 60 min, only 5-HT1BKO mice exhibited an impairment. At a delay of 90 min, all mice were impaired. Treatment by scopolamine (0.8 mg/kg) induced the same pattern of performance in wild type as did the mutation for short (5 min, no impairment) and long (60 min, impairment) delays. The 22-month-old wild-type and knockout mice exhibited an impairment at short delays (5 and 15 min). The effect of the mutation affected both young-adult and aged mice at delays of 15, 30, and 60 min. Neurobiological data show that stimulation of the 5-HT1B receptor inhibits the release of acetylcholine in the hippocampus, but stimulates this in the frontal cortex. This dual function might, at least in part, explain the opposite effect of the mutation on reference memory (facilitation) and delay-dependent working memory (impairment). These results support the idea that cholinergic-serotonergic interactions play an important role in memory processes.     

Bonobos and orangutans,but not chimpanzees,flexibly plan for the future in a token-exchange task

Non-human animals, including great apes, have been suggested to share some of the skills for planning that humans commonly exhibit. A crucial difference between human and non-human planning may relate to the diversity of domains and needs in which this skill is expressed. Although great apes can save tools for future use, there is little evidence yet that they can also do so in other contexts. To investigate this question further, we presented the apes with a planning token-exchange task that differed from standard tool-use tasks. Additionally, we manipulated the future outcome of the task to investigate planning flexibility. In the Exchange condition, subjects had to collect, save and transport tokens because they would need them 30 min later to exchange them for food with a human, i.e., “bring-back” response. In the Release condition, the collection and transport of tokens were not needed as no exchange took place after 30 min. Out of 13 subjects, eight solved the task at least once in the Exchange condition, with chimpanzees appearing less successful than the other species. Importantly, three individuals showed a clear differential response between conditions by producing more “bring-back” responses in the Exchange than in the Release conditions. Those bonobo and orangutan individuals hence adapted their planning behavior according to changing needs (i.e., they brought tokens back significantly more often when they would need them). Bonobos and orangutans, unlike chimpanzees, planned outside the context of tool-use, thus challenging the idea that planning in these species is purely domain-specific.