Secondary rewards acquire enhanced incentive motivation via increasing anticipatory activity of the lateral orbitofrontal cortex.

The motivation to strive for and consume primary rewards such as palatable food is bound by devaluation mechanisms, yet secondary rewards such as money may not be bound by these regulatory mechanisms. The present study therefore aimed at determining diverging devaluation trajectories for primary (chocolate milk) and secondary (money) reinforcers on the behavioral and neural level. Devaluation procedures with repeated exposure to reward combined with a choice (Experiment 1) and an incentive delay (Experiment 2) paradigm consistently revealed decreasing hedonic value for the primary reward as reflected by decreasing hedonic evaluation and choice preference with repeated receipt, while hedonic value and preferences for the secondary reward increased. Concomitantly acquired functional near-infrared spectroscopy (fNIRS) data during the incentive delay paradigm revealed that increasing value of the secondary reward was accompanied by increasing anticipatory activation in the lateral orbitofrontal cortex, while during the consummatory phase the secondary reinforcer associated with higher medial orbitofrontal activity irrespective of devaluation stage. Overall, the findings suggest that-in contrast to primary reinforcers-secondary reinforcers, i.e. money, can acquire progressively enhanced incentive motivation with repeated receipt, suggesting a mechanism which could promote escalating striving to obtain secondary rewards.

Depression uncouples brain hate circuit.

It is increasingly recognized that we need a better understanding of how mental disorders such as depression alter the brain's functional connections to improve both early diagnosis and therapy. A new holistic approach has been used to investigate functional connectivity changes in the brains of patients suffering from major depression using resting-state functional magnetic resonance imaging (fMRI) data. A canonical template of connectivity in 90 different brain regions was constructed from healthy control subjects and this identified a six-community structure with each network corresponding to a different functional system. This template was compared with functional networks derived from fMRI scans of both first-episode and longer-term, drug resistant, patients suffering from severe depression. The greatest change in both groups of depressed patients was uncoupling of the so-called 'hate circuit' involving the superior frontal gyrus, insula and putamen. Other major changes occurred in circuits related to risk and action responses, reward and emotion, attention and memory processing. A voxel-based morphometry analysis was also carried out but this revealed no evidence in the depressed patients for altered gray or white matter densities in the regions showing altered functional connectivity. This is the first evidence for the involvement of the 'hate circuit' in depression and suggests a potential reappraisal of the key neural circuitry involved. We have hypothesized that this may reflect reduced cognitive control over negative feelings toward both self and others.

Roles of α- and ß-estrogen receptors in mouse social recognition memory: effects of gender and the estrous cycle.

Establishing clear effects of gender and natural hormonal changes during female ovarian cycles on cognitive function has often proved difficult. Here we have investigated such effects on the formation and long-term (24 h) maintenance of social recognition memory in mice together with the respective involvement of α- and ß-estrogen receptors using α- and ß-estrogen receptor knockout mice and wildtype controls. Results in wildtype animals showed that while females successfully formed a memory in the context of a habituation/dishabituation paradigm at all stages of their ovarian cycle, only when learning occurred during proestrus (when estrogen levels are highest) was it retained after 24 h. In α-receptor knockout mice (which showed no ovarian cycles) both formation and maintenance of this social recognition memory were impaired, whereas ß-receptor knockouts showed no significant deficits and exhibited the same proestrus-dependent retention of memory at 24 h. To investigate possible sex differences, male α- and ß-estrogen receptor knockout mice were also tested and showed similar effects to females excepting that α-receptor knockouts had normal memory formation and only exhibited a 24 h retention deficit. This indicates a greater dependence in females on α-receptor expression for memory formation in this task. Since non-specific motivational and attentional aspects of the task were unaffected, our findings suggest a general α-receptor dependent facilitation of memory formation by estrogen as well as an enhanced long-term retention during proestrus. Results are discussed in terms of the differential roles of the two estrogen receptors, the neural substrates involved and putative interactions with oxytocin.

Human amygdala reactivity is diminished by the ß-noradrenergic antagonist propranolol.

BACKGROUND: Animal models of anxiety disorders emphasize the crucial role of locus ceruleus-noradrenergic (norepinephrine, NE) signaling, the basolateral amygdala (BLA) and their interactions in the expression of anxiety-like behavioral responses to stress. Despite clinical evidence for the efficacy of a ß-noradrenergic receptor blockade with propranolol in the alleviation of anxiety symptoms and the secondary prevention of post traumatic stress disorder, preclinical evidence for a ß-noradrenergic modulation of BLA activity in humans is missing. METHOD: We combined functional magnetic resonance imaging in healthy volunteers with probabilistic mapping of intra-amygdalar responses to fearful, neutral and happy facial expressions to test the hypothesis that a ß-noradrenergic receptor blockade with propranolol would inactivate the BLA. RESULTS: Consistent with our a priori hypothesis, propranolol diminished BLA responses to facial expressions, independent of their emotional valence. The absence of activity changes in probabilistically defined visual control regions underscores the specific action of propranolol in the BLA. CONCLUSIONS: Our findings provide the missing link between the anxiolytic potential of propranolol and the biological basis of ß-noradrenergic activation in the human BLA as a key target for the pharmacological inhibition of anxiety neurocircuitry. Moreover, our findings add to emerging evidence that NE modulates both the reactivity (sensitivity) and the operating characteristics (specificity) of the BLA via ß-noradrenergic receptors.

Effects of anesthetic agents on socially transmitted olfactory memories in mice.

Mice can learn a food preference from odor cues transmitted on the breath of a conspecific, even if the "demonstrator" is anesthetized. To our knowledge there are no studies examining the effect of anesthetizing the "observer" on development of memory for socially transmitted food preferences (STFP). In Experiment 1 we found that 2-4 month-old F2 C57Bl/6x129sv male and female mice demonstrated a STFP after a 5min exposure to an anesthetized demonstrator mouse when tested 24h later. In Experiment 2, observer mice anesthetized with Sagatal (60 mg/kg) prior to the "social interaction" preferentially avoided the cued food when tested 24h later. This aversion was not due to any overt aversive effects of this dose of Sagatal because mice that ate the food and were then anesthetized, or could only smell the food for 5 min while anesthetized, showed no preference or aversion. In a third experiment we found that the Sagatal-induced aversion was not a general property of anesthesia because there were varied results produced by observer mice treated with anesthetic drugs with different mechanisms of action. Vetalar (200mg/kg) and Rompun (10 mg/kg) treated animals ate similar amounts of cued and non-cued food at test, indicating an absence of learning. Hypnorm (0.5 ml/kg) treated animals showed a preference for the cued food whereas those treated with Hypnovel (2.5 ml/kg) showed an aversion to the cued food. These results show that the food aversion observed with Sagatal is not a general property of anesthetic agents, but appears to be restricted to those acting primarily on the GABAergic system. Thus, we have shown that under certain conditions it is possible for an anesthetized observer mouse to learn a preference or aversion of a socially-linked olfactory cue.

Estradiol prevents ozone-induced increases in brain lipid peroxidation and impaired social recognition memory in female rats.

There is increasing concern about the neurodegenerative and behavioral consequences of ozone pollution in industrialized urban centers throughout the world and that women may be more susceptible to brain neurodegenerative disorders. In the present study we have investigated the effects of chronic (30 or 60 days) exposure to ozone on olfactory perception and memory and on levels of lipid peroxidation, alpha and beta estrogen receptors and dopamine beta-hydroxylase in the olfactory bulb in ovariectomized female rats. The ability of 17beta-estradiol to prevent these effects was then assessed. Results showed that ozone exposure for 30 or 60 days impaired formation/retention of a selective olfactory recognition memory 120 min after exposure to a juvenile stimulus animal with the effect at 60 days being significantly greater than at 30 days. They also showed impaired speed in locating a buried chocolate reward after 60 days of ozone exposure indicating some loss of olfactory perception. These functional impairments could all be prevented by coincident estradiol treatment. In the olfactory bulb, levels of lipid peroxidation were increased at both 30- and 60-day time-points and numbers of cells with immunohistochemical staining for alpha and beta estrogen receptors, and dopamine beta-hydroxylase were reduced as were alpha and beta estrogen receptor protein levels. These effects were prevented by estradiol treatment. Oxidative stress damage caused by chronic exposure to ozone does therefore impair olfactory perception and social recognition memory and may do so by reducing noradrenergic and estrogen receptor activity in the olfactory bulb. That these effects can be prevented by estradiol treatment suggests increased susceptibility to neurodegenerative disorders in aging women may be contributed to by reduced estrogen levels post-menopause.

Vaginocervical stimulation enhances social recognition memory in rats via oxytocin release in the olfactory bulb.

The ability of vaginocervical stimulation (VCS) to promote olfactory social recognition memory at different stages of the ovarian cycle was investigated in female rats. A juvenile social recognition paradigm was used and memory retention tested at 30 and 300 min after an adult was exposed to a juvenile during three 4-min trials. Results showed that an intact social recognition memory was present at 30 min in animals with or without VCS and at all stages of the estrus cycle. However, whereas no animals in any stage of the estrus cycle showed retention of the specific recognition memory at 300 min, those in the proestrus/estrus phase that received VCS 10 min before the trial started did. In vivo microdialysis studies showed that there was a significant release of oxytocin after VCS in the olfactory bulb during proestrus. There was also increased oxytocin immunoreactivity within the olfactory bulb after VCS in proestrus animals compared with diestrus ones. Furthermore, when animals received an infusion of an oxytocin antagonist directly into the olfactory bulb, or a systemic administration of alpha or beta noradrenaline-antagonists, they failed to show evidence for maintenance of a selective olfactory recognition memory at 300 min. Animals with vagus or pelvic nerve section also showed no memory retention when tested after 300 min. These results suggest that VCS releases oxytocin in the olfactory bulb to enhance the social recognition memory and that this may be due to modulatory actions on noradrenaline release. The vagus and pelvic nerves are responsible for carrying the information from the pelvic area to the CNS.

Soluble amyloid beta1-42 reduces dopamine levels in rat prefrontal cortex: relationship to nitric oxide.

Several studies suggest a pivotal role of amyloid beta (Abeta)(1-42) and nitric oxide (NO) in the pathogenesis of Alzheimer's disease. NO also possess central neuromodulatory properties. To study the soluble Abeta(1-42) effects on dopamine concentrations in rat prefrontal cortex, microdialysis technique was used. We showed that i.c.v. injection or retrodialysis Abeta(1-42) administration reduced basal and K(+)-stimulated dopamine levels, measured 2 and 48 h after peptide administration. Immunofluorescent experiments revealed that after 48 h from i.c.v. injection Abeta(1-42) was no longer detectable in the ventricular space. We then evaluated the role of NO on Abeta(1-42)-induced reduction in dopamine concentrations. Subchronic L-arginine administration decreased basal dopamine levels, measured either 2 h after i.c.v. Abeta(1-42) or on day 2 post-injection, whereas subchronic 7-nitroindazole administration increased basal dopamine concentrations, measured 2 h after i.c.v. Abeta(1-42) injection, and decreased them when measured on day 2 post-Abeta(1-42)-injection. No dopaminergic response activity was observed after K(+) stimulation in all groups. These results suggest that the dopaminergic system seems to be acutely vulnerable to soluble Abeta(1-42) effects. Finally, the opposite role of NO occurring at different phases might be regarded as a possible link between Abeta(1-42)-induced effects and dopaminergic dysfunction.

Spike sorting based upon machine learning algorithms (SOMA).

We have developed a spike sorting method, using a combination of various machine learning algorithms, to analyse electrophysiological data and automatically determine the number of sampled neurons from an individual electrode, and discriminate their activities. We discuss extensions to a standard unsupervised learning algorithm (Kohonen), as using a simple application of this technique would only identify a known number of clusters. Our extra techniques automatically identify the number of clusters within the dataset, and their sizes, thereby reducing the chance of misclassification. We also discuss a new pre-processing technique, which transforms the data into a higher dimensional feature space revealing separable clusters. Using principal component analysis (PCA) alone may not achieve this. Our new approach appends the features acquired using PCA with features describing the geometric shapes that constitute a spike waveform. To validate our new spike sorting approach, we have applied it to multi-electrode array datasets acquired from the rat olfactory bulb, and from the sheep infero-temporal cortex, and using simulated data. The SOMA sofware is available at http://www.sussex.ac.uk/Users/pmh20/spikes.

Applications of multi-variate analysis of variance (MANOVA) to multi-electrode array electrophysiology data.

We have developed an adaptation of multi-variate analysis of variance (MANOVA) to analyze statistically both local and global patterns of multi-electrode array (MEA) electrophysiology data where the activities of many (typically >100) neurons have been recorded simultaneously. Whereas simple application of standard MANOVA techniques prohibits extraction of useful information in this kind of data, our new approach, MEANOVA (=MEA+MANOVA), allows a more useful and powerful approach to analyze such complex neurophysiological data. The MEANOVA test enables the detection of the "hot-spots" in the MEA data and has been validated using recordings from the rat olfactory bulb. To further validate the power of this approach, we have also applied the MEANOVA test to data obtained from a simple computational network model. This MEANOVA software and other useful statistical methods for MEA data can be downloaded from http://www.sussex.ac.uk/Users/pmh20

Effect of LTP-reinforcing paradigms on neurotransmitter release in the dentate gyrus of young and aged rats.

Long-term potentiation (LTP) is considered a cellular correlate of memory processing. A short-lasting early-LTP can be prolonged into a late-L TP (>4h) by stimulation of the basolateral amygdala (BLA) or motivational behavioral stimuli in young, but not in aged, cognitively impaired rats. We measured the changes in transmitter release-induced by BLA or behavioral reinforcement-in young and aged cognitively impaired rats, after implanting a microdialysis cannula at the dentate gyrus. Samples were taken under baseline conditions and during stimulation of BLA. Rats were water deprived and tested again next day, taking samples after allowing access to water. Higher concentrations of choline, HIAA, aspartate, glutamate, and glycine were found in baseline samples from young animals compared to aged. In young animals, BLA stimulation increased the levels of ACh and reduced norepinephrine and serotonine, while behavioral reinforcement reduced the levels of glutamate and glycine. These effects were absent among aged rats, suggesting that this reduced neurochemical response might be linked to the impaired LTP-reinforcement reported previously.

Amino acid neurotransmitter release and learning: a study of visual imprinting.

The intermediate and medial part of the hyperstriatum ventrale (IMHV) is an area of the domestic chick forebrain that stores information acquired through the learning process of imprinting. The effects of visual imprinting on the release of the amino acids aspartate, arginine, citrulline, gamma-aminobutyric acid (GABA), glutamate, glycine and taurine from the left and right IMHVs in vitro were measured at 3.5, 10 and 24 h after training. Chicks were exposed to an imprinting stimulus for 1 h, their preferences measured 10 min afterward and a preference score calculated as a measure of the strength of learning. Potassium stimulation was used to evoke amino acid release from the IMHVs of trained and untrained chicks in the presence and absence of extracellular Ca2+. Ca2+-dependent, K+-evoked release of glutamate was significantly (34.4%) higher in trained than in untrained chicks. This effect was not influenced by time after training or by side (left or right IMHV). Training influenced the evoked release of GABA and taurine from the left IMHV at both 3.5 and 10 h. The training effects at the two times were statistically homogeneous so data (< or = 10 h group) were combined for each amino acid respectively. For this < or = 10 h group, evoked release increased significantly with preference score. In contrast, for the 24 h group, evoked release of GABA and taurine was not significantly correlated with preference score. There were no significant correlations between preference score and GABA or taurine release in the right IMHV at any time, nor in the absence of extracellular calcium. No significant effects of training condition, time or side were observed for any other amino acid in the study. The present findings suggest that soon after chicks have been exposed to an imprinting stimulus glutamatergic excitatory transmission in IMHV is enhanced, and remains enhanced for at least 24 h. In contrast, the learning-related elevations in taurine and GABA release are not sustained over this period. The change in GABA release may reflect a transient increase in inhibitory transmission in the left IMHV.

Somatostatin induces striatal dopamine release and contralateral turning behaviour in the mouse.

Application of somatostatin to the striatum of the anaesthetized rat has previously been shown to elicit large increases in extracellular levels of dopamine and GABA via a glutamate-dependent mechanism. These actions have been ascribed to the SSTR2 receptor. Here we describe experiments designed to investigate whether these effects occur in C57Bl6 mice and if they elicit rotational behaviours associated with increased dopamine in the striatum. Application of somatostatin resulted in increased concentrations of dopamine in striatum, hippocampus and amygdala of anaesthetized mice. Unilateral striatal infusions of the peptide by retrodialysis increased locomotion. Application of N-methyl-D-aspartate and AMPA to the freely-moving mouse striatum resulted in increased dopamine release; however, only AMPA caused increased locomotion. These results further confirm that somatostatin can play a role in the control of locomotor function by modulating striatal dopamine release.

Involvement of the medial prefrontal cortex in mediating behavioural responses to odour cues rather than olfactory recognition memory.

Sheep form an olfactory recognition memory for their lambs within 2 h of parturition and will subsequently reject the approaches of any strange lamb and protest vocally. In this study we report that following olfactory memory formation, ewes exposed to either their own or a strange lamb show c-fos mRNA expression in the medial frontal cortex, although levels of expression in the pyramidal output cell layer V were significantly higher in ewes that rejected strange lambs. Reversibly inactivating this region by the retrodialysis of the anaesthetic tetracaine before birth reduced aggressive motor responses towards lambs but not protest vocalisations. Similar treatment during the critical period for olfactory memory formation and lamb recognition (0-4 h post-partum) had no effect on ewes maternal behaviour towards their own lambs. It did, however, prevent the normal selective expression of aggressive rejection, and reduced protest vocalisation behaviours directed towards strange lambs. These rejection behaviours did appear 1 h after the termination of tetracaine infusions despite the ewes not being given the opportunity to interact with their own lambs during this time. Therefore, tetracaine blockade of the medial frontal cortex prevents animals from responding with motor aggression, but not vocal aggression, to odour cues from strange lambs, but has no effect on the formation of an olfactory recognition memory for their own lambs. Both pre- and post-partum aggressive rejection of strange lambs was associated with increased concentrations of dopamine, serotonin, glutamate and GABA. When these behaviours were inhibited by the tetracaine infusions, extracellular concentrations of these neurotransmitters were all increased by the anaesthetic but did not change in response to lambs. These findings suggest that a functional medial frontal cortex is not required for the formation of an olfactory recognition memory or for mediating pro-active maternal behaviours. It is however required for the mediation of motor but not vocal aspects of aggressive rejection responses directed towards aversive odour cues from strange lambs.

Sheep don't forget a face.

The human brain has evolved specialized neural mechanisms for visual recognition of faces, which afford us a remarkable ability to discriminate between, remember and think about many hundreds of different individuals. Sheep also recognize and are attracted to individual sheep and humans by their faces, as they possess similar specialized neural systems in the temporal and frontal lobes for assisting in this important social task, including a greater involvement of the right brain hemisphere. Here we show that individual sheep can remember 50 other different sheep faces for over 2 years, and that the specialized neural circuits involved maintain selective encoding of individual sheep and human faces even after long periods of separation.

Somatostatin release by glutamate in vivo is primarily regulated by AMPA receptors.

1. We have used in vivo microdialysis in anaesthetized rats to investigate whether levels of striatal somatostatin (SRIF) can be increased in response to application of the ionotropic glutamate receptor agonists AMPA and NMDA. 2. Application of both AMPA and NMDA (10, 50, 100 and 500 microM) for 20 min periods produced concentration-dependent increases in the extracellular levels of SRIF. A 500 microM dose of each compound was shown to be the most potent concentration tested, increasing levels of SRIF by 32 fold (NMDA) and 35 fold (AMPA). At lower concentrations (10 microM) NMDA failed to evoke significant amounts of SRIF while AMPA increased levels of the peptide 2.3 fold. 3. Application of the respective receptor antagonists APV (NMDA receptor) and DNQX (AMPA receptor) abolished the abilities of the agonists to evoke release of SRIF. Interestingly DNQX abolished the ability of NMDA to evoke release of the peptide as well. 4. The ability of both AMPA and NMDA to evoke increases in the levels of extracellular SRIF further illustrates the reciprocal relationship that exists between SRIF and glutamate in the striatum which impacts particularly on dopaminergic functioning in this region.

GABA, taurine and learning: release of amino acids from slices of chick brain following filial imprinting.

The intermediate and medial hyperstriatum ventrale (IMHV) is a forebrain region in the domestic chick that is a site of information storage for the learning process of imprinting. We enquired whether imprinting is associated with learning-related increases in calcium-dependent, potassium-stimulated release of neurotransmitter amino acids from the IMHV. Chicks were hatched and reared in darkness until 15-30 h after hatching. They then either remained in darkness or were trained for 2 h by exposure to an imprinting stimulus. One hour later, the chicks were given a preference test and a preference score was calculated from the results of this test, as a measure of imprinting. Chicks were killed 2 h after training. Slices from the left and right IMHV of trained and untrained chicks were superfused with Krebs' solution either with or without calcium and the superfusate assayed for arginine, aspartate, citrulline, GABA, glutamate, glycine and taurine using high-performance liquid chromatography. For calcium-containing superfusates from the left IMHV, preference score was significantly correlated with potassium-stimulated release of (i) GABA (r=0.51, 23 d.f., P=0.008) and (ii) taurine (r=0.77, 23 d.f., P<0.0001). There was no significant difference between the mean values of trained and untrained chicks for either compound. However, examination of the variance of the data indicated that release of both GABA and taurine increased as a result of learning. No significant correlation between preference score and release was found for any of the amino acids from the right IMHV, nor for control tissue from the left IMHV superfused with calcium-free solution. These results demonstrate that the learning process of imprinting is associated with increases in releasable pools of GABA and taurine and/or membrane excitability in the left IMHV.

Sex differences in the influence of mothers on the sociosexual preferences of their offspring.

The extent to which "nurture" as opposed to "nature" determines behavior and sociosexual preferences in mammalian species is controversial although most recent interest has focused on genetic determinants. We report here that if sheep and goats are cross-fostered at birth, but raised in mixed-species groups, their play and grooming behavior resembles that of their foster rather than genetic species. There are no sex differences in effects on these behaviors, and other species-specific behavior patterns such as aggression, browsing, climbing, and vocalizations are unaffected. In adulthood, cross-fostered males strongly prefer to socialize and mate with females of their foster mother's species, even if raised with a conspecific of their own species. Castration within 2 days of birth slightly reduces the level of this altered social preference but mating preference following short-term testosterone treatment is the same as for gonadally intact animals. Cross-fostered females also show significant preference for socializing with females and mating with males of their foster mother's species, although this effect is weaker than that in both gonadally intact and castrated males. When cross-fostered animals are placed in flocks containing members of only their genetic species for 3 years, male social and mating preferences for females of their mother's species remain virtually unaffected. Females change to display an exclusive mating preference for members of their genetic species in 1-2 years although they still retain some social interest in female members of their foster species. Thus, there are clear sex differences in the impact of the emotional bond between a mother and her offspring in these mammals. Effects on males are strongest and irreversibly maintained even after altering their social environment, whereas those on females are weaker and mating preferences are clearly adaptable in the face of altered social priorities. These sex differences are presumably caused by pre-, or early postnatal, organizational effects of sex hormones on the brain.

Effects of ENA713 and CHF2819, two anti-Alzheimer's disease drugs, on rat amino acid levels.

The effects of oral ENA713 and CHF2819 (0.5, 1.5 and 4.5 mg/kg), two novel acetylcholinesterase inhibitors, on extracellular concentrations of amino acids in rat hippocampus, were evaluated using in vivo microdialysis. ENA713, at 4.5 mg/kg, but not CHF2819, significantly decreased glutamate, taurine, arginine and citrulline levels, without affecting aspartate concentrations. These results suggest that the modulation of amino acidergic transmission could represent an additional mechanism of action in Alzheimer's disease for some acetylcholinesterase inhibitors.

Human face recognition in sheep: lack of configurational coding and right hemisphere advantage.

Face recognition in sheep is qualitatively similar to that in humans in terms of its left visual field bias, and the effects of expertise and configural coding. The current study was designed to determine whether such effects are species specific by investigating the case of sheep recognising humans. It was found that the sheep could identify human faces and while they showed a small inversion-induced decline in discriminatory performance, this was significantly less than seen with sheep faces. In other aspects, there were qualitative differences with human face recognition compared with conspecific recognition. In contrast with sheep faces there was no left visual field advantage in the recognition of human faces and the internal features were not used at all as visual cues. The data suggest that these sheep, whilst being extensively exposed to interactions with humans, were unable to identify them with all the same 'expert' methods as were used to discriminate other sheep. This suggests that different neural systems may, to some extent, be used for recognition of sheep as opposed to human faces. The relative contribution to differential neural processing of the faces of the different species and the role of expertise are discussed.