Lesions of the orbital prefrontal cortex impair the formation of attentional set in rats.

In rats, reversal learning impairments are commonly reported after lesions of the orbital prefrontal cortex (OFC), in contrast to the effect of lesions of the medial prefrontal cortex, which impair attentional set-shifting. Comparable dissociations have also been reported in humans, monkeys and mice. However, these two manifestations of behavioural flexibility may share common cognitive processes. The present study tested the hypothesis that lesions of the OFC (an area that integrates expected and actual outcomes to signal which cues in the environment predict reward) would impair the formation of attentional set as well as impairing reversal learning. We compared the performance of lesioned and control rats on two set-shifting tasks. The first task we used, 'the 4ID task', had no reversal stages, but multiple intradimensional acquisitions before the extradimensional shift stage, to assess set-formation as well as set-shifting. The second task was the standard intradimensional/extradimensional '7-stage task', which includes reversal learning stages after each compound acquisition. Compared with controls, lesioned rats were slower to form attentional set on the 4ID task. When they did form a set, they required more trials to complete the extradimensional shift stage. On the 7-stage task, we replicated our previous finding of impaired reversal learning and reduced shift-costs. We interpret these findings as reflecting a single deficit in identifying relevant cues after unexpected outcomes, which supports recent models of OFC function. Our findings challenge the assumption that the contribution of the OFC to behavioural flexibility is limited to reversal learning.

The effects of DISC1 risk variants on brain activation in controls, patients with bipolar disorder and patients with schizophrenia.

Three risk variants (rs1538979, rs821577, and rs821633) in the Disrupted-in-Schizophrenia-1 (DISC1) gene have previously been associated with both schizophrenia and bipolar disorder in a recent collaborative analysis of European cohorts. In this study we examined the effects of these risk variants on brain activation during functional magnetic resonance imaging (fMRI) of the Hayling Sentence Completion Task (HSCT) in healthy volunteers (n=33), patients with schizophrenia (n=20) and patients with bipolar disorder (n=36). In the healthy controls the risk associated allele carriers of SNPs rs1538979 and rs821633 demonstrated decreased activation of the cuneus. Moreover, there was an effect of SNP rs1538979 in the pre/postcentral gyrus with decreased activation in healthy controls and increased activation in patients with schizophrenia. In the bipolar group there was decreased activation in the risk carriers of SNP rs821633 in the inferior parietal lobule and left cingulate cortex. Clusters in the precentral gyrus, left middle temporal gyrus and left cerebellum were found to be significant on examining the group × genotype interactions. These findings may provide a better understanding of the neural effects of DISC1 variants and on the pathophysiology of schizophrenia and bipolar disorder.

Inhibition of thalamic excitability by 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-3-ol: a selective role for delta-GABA(A) receptors.

The sedative and hypnotic agent 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-3-ol (THIP) is a GABA(A) receptor (GABA(A)R) agonist that preferentially activates delta-subunit-containing GABA(A)Rs (delta-GABA(A)Rs). To clarify the role of delta-GABA(A)Rs in mediating the sedative actions of THIP, we utilized mice lacking the alpha(1)- or delta-subunit in a combined electrophysiological and behavioural analysis. Whole-cell patch-clamp recordings were obtained from ventrobasal thalamic nucleus (VB) neurones at a holding potential of -60 mV. Application of bicuculline to wild-type (WT) VB neurones revealed a GABA(A)R-mediated tonic current of 92 +/- 19 pA, which was greatly reduced (13 +/- 5 pA) for VB neurones of delta(0/0) mice. Deletion of the delta- but not the alpha(1)-subunit dramatically reduced the THIP (1 mum)-induced inward current in these neurones (WT, -309 +/- 23 pA; delta(0/0), -18 +/- 3 pA; alpha(1) (0/0), -377 +/- 45 pA). Furthermore, THIP selectively decreased the excitability of WT and alpha(1) (0/0) but not delta(0/0) VB neurones. THIP did not affect the properties of miniature inhibitory post-synaptic currents in any of the genotypes. No differences in rotarod performance and locomotor activity were observed across the three genotypes. In WT mice, performance of these behaviours was impaired by THIP in a dose-dependent manner. The effect of THIP on rotarod performance was blunted for delta(0/0) but not alpha(1) (0/0) mice. We previously reported that deletion of the alpha(1)-subunit abolished synaptic GABA(A) responses of VB neurones. Therefore, collectively, these findings suggest that extrasynaptic delta-GABA(A)Rs vs. synaptic alpha(1)-subunit-containing GABA(A)Rs of thalamocortical neurones represent an important molecular target underpinning the sedative actions of THIP.

More rapid reversal learning following overtraining in the rat is evidence that behavioural and cognitive flexibility are dissociable.

Cognitive flexibility is a term used to describe the brain processes underlying the phenomenon of adaptive change in behaviour in response to changed contingencies in the internal or external environment. Cognitive flexibility is often assessed in complex tasks measuring perceptual attentional shifting or response or task switching, but, arguably, reversal learning is a simple assay of cognitive flexibility. Reversal learning requires the detection of a changed outcome, the cessation of a previously-rewarded response and the selection of an alternative, previously-unrewarded, response. This study addressed the issue of the relationship between reversal learning and cognitive flexibility. In a single testing session, rats completed a series of 2-alternative forced-choice discriminations between digging bowls. The bowls differed according to both the medium within the bowl and the odor of the bowl. Having learned which cue (one of the odors or one of the digging media) indicated the food-baited bowl, half the rats were given additional trials of "over-training". To test reversal learning, the meaning of the cues predictive of reward/non-reward was then switched. There was a robust effect of over-training, with over-trained rats performing reversal learning in fewer trials than rats trained to criterion only. The pattern of errors supported the hypothesis that more rapid reversing results from the formation of an attentional set. This is the same attentional mechanism that results in less rapid shifting or switching. We conclude that the behavioural flexibility demonstrated in reversal learning does not provide a scale on which cognitive flexibility can be measured.

Food or friends? What motivates zebrafish (Danio rerio) performing a visual discrimination.

As a model organism, zebrafish have much to offer neuroscientific research and they are increasingly being used in behavioral neuroscience, for example to study the genetics of learning and memory. As fish are often considered "less clever" than mammals, it is important to understand how they learn and to establish optimal testing conditions. In this study, we compared the efficacy of food reinforcement and social stimuli in supporting Pavlovian conditioning, Pavlovian-to-instrumental transfer, and acquisition of a two-alternative forced choice visual discrimination. Although equally effective in conditioning and in motivating discrimination learning, fish responded with shorter latencies when they were anticipating food but responded for a greater number of trials when anticipating the social stimulus. After learning, the reward was changed: food-reinforcement was replaced with the social stimulus and vice versa. Performance accuracy did not change, but response latency did: the group previously rewarded with food, but now rewarded with the social stimulus, showed a decrease in response vigor. This is a negative contrast effect, which is well established in rats, but was thought to be absent in fish because they lacked goal representation. Our results show that zebrafish, like rats, do have goal representations. Furthermore, we have shown that whereas food has greater incentive salience than social stimuli, fish become satiated rapidly, but motivation to seek social stimuli is sustained. We conclude that zebrafish are well motivated by a mixed economy of social stimuli and food.

Exacerbation of the credit assignment problem in rats with lesions of the medial prefrontal cortex is revealed by Bayesian analysis of behavior in the pre-solution period of learning.

Our internal models of the world help us to process information rapidly: in general model-based learning is more rapid than model-free learning. However, the cognitive flexibility required to overcome cognitive predispositions can let us down: it is not fully developed until adulthood; predispositions can be unconscious biases; and cognitive flexibility is impaired in many psychiatric and neurological conditions. To understand these limits to flexibility, we need to know how the brain generates predispositions and deploys flexibility. We performed a detailed analysis of the exploratory behavior of rats in the pre-solution period of a two-alternative forced choice discrimination learning task. Rats readily learn in which of two bowls, filled with differentially scented and textured digging materials, there is hidden bait. In a single session, they are presented with a series of discrimination learning and reversal stages. We performed a simple Bayesian analysis on the data from 68 rats, 33 of which had lesions of the medial prefrontal cortex, to examine patterns of responding in the pre-solution period. Control rats rapidly focussed on the relevant stimulus attributes and showed flexibility when required to learn about a different stimulus attribute. Rats with prefrontal cortex damage had reduced sensitivity to negative feedback. They were able to overcome this deficit and solve the credit assignment problem when there were limited alternatives or when attention was appropriately focused and predispositions matched the required response. However, the learning impairment presents as a problem with shifting attention due to the additional difficulty of solving the credit assignment problem when the attentional set is inconsistent with the required response.

Lesions of the basal forebrain impair reversal learning but not shifting of attentional set in rats.

The cholinergic neurons of the basal forebrain, which project to cortex, the thalamic reticular nucleus and the amygdala, are implicated in many aspects of attentional function, while the intrinsic neurons of the basal forebrain are implicated in learning and memory. This study compared the effects of lesions of the basal forebrain made with either the immunotoxin 192-IgG-saporin (which selectively destroys cholinergic neurons), or the non-selective excitotoxin, ibotenic acid (which destroys both cholinergic and non-cholinergic neurons) on a task which measure the acquisition and shifting of attentional set as well as the ability to learn reversals of specific stimulus-reward pairings. Rats learned to obtain food reward by digging in small bowls containing distinctive digging media that were differentially scented with distinct odours. They performed a series of two-choice discriminations, with the bait associated with either the odour or the digging medium. Rats with 192-IgG-saporin lesions of the basal forebrain were not impaired relative to control rats at any stage of the task. Rats with ibotenic acid lesions of the basal forebrain were impaired the first time stimulus-reward contingencies were reversed. They were not impaired in acquisition of new discriminations, even when an attentional-shift was required. These data are consistent with data from marmosets and so highlight the functional similarity of monkey and rodent basal forebrain. They also confirm the likely involvement of non-cholinergic neurons of the basal forebrain in reversal learning.

Assessment of intradimensional/extradimensional attentional set-shifting in rats.

The rat intradimensional/extradimensional (ID/ED) task, first described by Birrell and Brown 18 years ago, has become the predominant means by which attentional set-shifting is investigated in rodents: the use of rats in the task has been described in over 135 publications by researchers from nearly 90 universities and pharmaceutical companies. There is variation in the protocols used by different groups, including differences in apparatus, stimuli (both stimulus dimensions and exemplars within), and also the methodology. Nevertheless, most of these variations seem to be of little consequence: there is remarkable similarity in the profile of published data, with consistency of learning rates and in the size and reliability of the set-shifting and reversal 'costs'. However, we suspect that there may be inconsistent data that is unpublished or perhaps 'failed experiments' that may have been caused by unintended deviations from effective protocols. The purpose of this review is to describe our approach and the rationale behind certain aspects of the protocol, including common pitfalls that are encountered when establishing an effective local protocol.

Oral dosing of rodents using a palatable tablet.

RATIONALE: Delivering orally bioavailable drugs to rodents is an important component to investigating that route of administration in novel treatments for humans. However, the traditional method of oral gavage requires training, is stressful, and can induce oesophageal damage in rodents. OBJECTIVES: To demonstrate a novel administrative technique-palatable gelatine tablets-as a stress-free route of oral delivery. METHODS: Twenty-four male Lister hooded rats were sacrificed for brain tissue analysis at varying time-points after jelly administration of 30 mg/kg of the wake-promoting drug modafinil. A second group of 22 female rats were tested on locomotor activity after 30 mg/kg modafinil, or after vehicle jellies, with the locomotor data compared to the brain tissue concentrations at the corresponding times. RESULTS: Modafinil was present in the brain tissue at all time-points, reducing in concentration over time. The pattern of brain tissue modafinil concentration is comparable to previously reported results following oral gavage. Modafinil-treated rats were more active than control rats, with greater activity during the later time-periods-similar to that previously reported following intraperitoneal injection of 40 mg/kg modafinil. CONCLUSIONS: Palatable jelly tablets are an effective route of administration of thermally stable orally bioavailable compounds, eliminating the stress/discomfort and health risk of oral gavage and presenting as an alternative to previously reported palatable routes of administration where high protein and fat levels may adversely affect appetite for food reward, and uptake rate in the gastrointestinal tract.

Amphetamine and the adenosine A(2A) antagonist KW-6002 enhance the effects of conditional temporal probability of a stimulus in rats.

As the length of foreperiod preceding an imperative signal increases, reaction time decreases and anticipatory (prior to the signal) responding increases. The authors designed a task to dissociate the effect of elapsing time in the foreperiod and conditional temporal probability of the imperative stimulus. The effects of 2 drugs--amphetamine and KW-6002--known to enhance the effect of foreperiod were compared. Three groups of rats were trained to respond to an auditory signal presented at 1 of 3 foreperiods, unpredictable from trial to trial. The length of preparation time was different for each group, but conditional temporal probability was the same. Reaction times were faster as a function of increased preparation time, whereas anticipatory responses were strongly modulated by conditional probability. Both amphetamine and KW-6002 speeded reaction times and increased anticipatory responding. The pattern of behavior was consistent with the suggestion that they enhanced the motor preparatory effects of conditional probability rather than speeded a timing process. The authors concluded that preparation time and expectancy (conditional temporal probability of an imperative signal) have differential effects on performance and that amphetamine and KW-6002 enhance the effect of expectancy.

Difficulty overcoming learned non-reward during reversal learning in rats with ibotenic acid lesions of orbital prefrontal cortex.

Behavioral flexibility is a concept often invoked when describing the function of the prefrontal cortex. However, the psychological substrate of behavioral flexibility is complex. Its key components are allocation of attention, goal-directedness, planning, working memory, and response selection. Furthermore, there is evidence that different regions of the prefrontal cortex might be implicated in these different components. In rule-switching tasks, a distinction is made between errors that are perseverative (difficulty switching from a previously rewarded strategy) and errors due to learned-irrelevance (difficulty switching to a strategy previously uncorrelated with reward). A similar distinction might be made for reversal learning, which involves inhibition of a previously rewarded response and activation of a previously unrewarded response. Damage to the orbital prefrontal cortex (OPFC) results in a deficit in reversal learning. The present study was designed to examine whether one or both of either perseveration or learned non-reward might account for the deficit. Rats with bilateral ibotenic acid-induced lesions of the OPFC were not impaired in acquisition of discriminations. They were impaired, relative to controls, only when they had to overcome learned non-reward. They did not show enhanced perseveration. We conclude that an inability to overcome learned non-reward significantly contributes to OPFC lesion-induced deficits in behavioral flexibility.

Effects of lesions of the subthalamic nucleus/zona incerta area and dorsomedial striatum on attentional set-shifting in the rat.

Patients with Parkinson's disease (PD) show cognitive impairments, including difficulty in shifting attention between perceptual dimensions of complex stimuli. Inactivation of the subthalamic nucleus (STN) has been shown to be effective in ameliorating the motor abnormalities associated with striatal dopamine (DA) depletion, but it is possible that STN inactivation might result in additional, perhaps attentional, deficits. This study examined the effects of: DA depletion from the dorsomedial striatum (DMS); lesions of the STN area; and the effects of the two lesions together, on the ability to shift attentional set in the rat. In a single session, rats performed the intradimensional/extradimensional (ID/ED) test of attentional set-shifting. This comprises a series of seven, two-choice discriminations, including acquisitions of novel discriminations in which the relevant stimulus is either in the currently attended dimension (ID) or the currently unattended dimension (ED shift) and reversals (REVs) following each acquisition stage. Bilateral lesions were made by injection of 6-hydroxydopamine (6-OHDA) into the DMS, resulting in a selective impairment in reversal learning. Large bilateral ibotenic acid lesions centered on the STN resulted in an increase in trials to criterion in the initial stages, but learning rate improved within the session. There was no evidence of a 'cost' of set-shifting - the ED stage was completed in fewer trials than the ID stage - and neither was there a cost of reversal learning. Strikingly, combined lesions of both regions did not resemble the effects of either lesion alone and resulted in no apparent deficits.

Understanding the relationship between suicidality, current depressed mood, personality, and cognitive factors.

OBJECTIVES: Links between suicidality and depressed mood are well established. There is, however, little information about the emotional regulation processes that underlie the relationship between suicidality and current low mood, and how these processes differ between groups of never-suicidal (NS), suicidal ideators, and suicide attempters. As suicidality and depression are heterogeneous constructs, this study aimed to conduct within- and between-group comparisons of known suicide risk factors that are associated with emotion regulation (neuroticism, trait aggression, brooding, impulsivity, and overgeneral autobiographical memories). DESIGN: Correlational design using between- and within-group comparisons from self-report measures. METHODS: Inter- and intragroup differences were identified using Pearson's correlation coefficients and tests of difference. An analysis of indirect effects was used to investigate whether the relationship between suicidality and current low mood was mediated by neuroticism, trait aggression, brooding, impulsivity, and overgeneral autobiographical memories, and if this relationship varied according to group type. RESULTS: Brooding appeared to be a consistent feature of all three groups and was closely related to current low mood. Compared to the NS group, the relationship between suicide attempts and current low mood showed greater associations with brooding, trait aggression, and overgeneral autobiographical memories. Compared to the NS group, the suicidal ideation group showed stronger associations with neuroticism and impulsivity, but these factors did not correlate with low mood. CONCLUSION: These results suggest a need for larger studies to focus on heterogeneity within suicidal populations and consider how different combinations of risk factors may heighten or reduce suicide risk. PRACTITIONER POINTS: It is well known that the severity and intensity of suicide and depressed presentations vary because of underlying dispositional and contextual factors (Fried & Nesse, ) which, in turn, affect how events are interpreted and responded to. Despite this, there is little research about how these mechanisms operate in different types of suicide groups, and their influence on the relationship between suicidality and current low mood. Understanding interrelationships that affect current low mood is of clinical significance because past suicidal history and deteriorations in already negative mood are linked to repeated suicide attempts and completion. Our findings show that ruminative brooding, defined as a tendency to repeatedly think about emotional aspects of an event, consistently correlates with current low mood across different types of suicidal groups (NS, suicidal ideators, and suicide attempters), and across analyses. Findings also show that suicidal ideation and attempt groups were associated with specific personality characteristics that increased the propensity of emotional responding and interpretation compared to the NS group. The relationship between suicide attempt and current low mood had a higher propensity to be influenced by trait aggression, brooding, and overgenerality compared to the NS group. In contrast, although the suicidal ideation group correlated more strongly with neuroticism and impulsivity, these factors did not influence current low mood. In terms of clinical practice, these findings imply that specific styles of interpretation and thinking may maintain the relationship between suicidality and current low mood. Given the cross-sectional nature of the study, however, it is not possible to imply causality. Nevertheless, the findings obtained provide some support for transdiagnostic models of cognitive-behavioural processes that could be developed further.

Rodent models of prefrontal cortical function.

In this article, we consider whether studies in rats can provide useful information regarding the debate about the functions of the primate prefrontal cortex. At a superficial level, comparison of regional specializations within the prefrontal cortices of different species suggests functional correspondence. Unfortunately, the nature of functional specialization in primate prefrontal cortex is controversial, and data supporting the idea of homology between specific areas of rat and primate prefrontal cortex are weak. Nevertheless, we argue here that studies of the computational functions within the relatively undifferentiated prefrontal cortex of rats can shed light on processing in primate prefrontal cortex.

The effect of the adenosine A(2A) antagonist KW-6002 on motor and motivational processes in the rat.

RATIONALE: It is well established that humans and rats respond to an imperative stimulus more rapidly as a function of the foreperiod preceding the target, and with this decrease in mean response time, there is also an increase in anticipatory (prior to the signal) responses. These changes reflect enhanced motor readiness. Also, reaction times are quicker when the cost of reward (amount of work required) is minimum. Antagonism of the adenosine A(2A) receptor has been shown to effect motor-related processes. OBJECTIVE: This study examined the behavioural effects of systemic administration of the adenosine A(2A) antagonist KW-6002 in a cued reaction time task in the rat. The purpose of this study is to ascertain whether KW-6002 would enhance motor readiness and effect performance as a function of reward cost. METHODS: Rats were trained on a visually cued reaction time task with variable foreperiods, and the effects of three doses of KW-6002 (0.3, 1.0 and 3.0 mg/kg systemically, compared to vehicle) were examined. RESULTS: Increasing doses of KW-6002 resulted in faster reaction times and an increase in the number of anticipatory responses. KW-6002 enhanced the foreperiod effect on reaction time distributions and anticipatory responses. In addition, KW-6002 had differential effects on performance between rewarded and unrewarded trials. CONCLUSION: Antagonism of adenosine A(2A) receptors by systemic KW-6002 speeds reaction time and enhanced motor preparatory processes as well as interacting with motivational processes.

Attentional Set-Shifting Across Species.

Attentional set-shifting, as a measure of executive flexibility, has been a staple of investigations into human cognition for over six decades. Mediated by the frontal cortex in mammals, the cognitive processes involved in forming, maintaining and shifting an attentional set are vulnerable to dysfunction arising from a number of human neurodegenerative diseases (such as Alzheimer's, Parkinson's and Huntington's diseases) and other neurological disorders (such as schizophrenia, depression, and attention deficit/hyperactivity disorder). Our understanding of these diseases and disorders, and the cognitive impairments induced by them, continues to advance, in tandem with an increasing number of tools at our disposal. In this chapter, we review and compare commonly used attentional set-shifting tasks (the Wisconsin Card Sorting Task and Intradimensional/Extradimensional tasks) and their applicability across species. In addition to humans, attentional set-shifting has been observed in a number of other animals, with a substantial body of literature describing performance in monkeys and rodents. We consider the task designs used to investigate attentional set-shifting in these species and the methods used to model human diseases and disorders, and ultimately the comparisons and differences between species-specific tasks, and between performance across species.

Vagal nerve stimulation: a review of its applications and potential mechanisms that mediate its clinical effects.

Vagal nerve stimulation (VNS) is an approved treatment for epilepsy and is currently under investigation as a therapy for other disorders, including depression, anxiety and Alzheimer's disease. This review examines the pre-clinical and clinical literature relating to VNS. A brief historical perspective is given, followed by consideration of the efficacy of the various clinical applications of VNS. Finally, what is known about the mechanism by which VNS exerts clinical benefit is considered. It is concluded that although the precise mechanism of action of VNS is still unknown, the search for the mechanism has the potential to lend new insight into the neuropathology of depression. It is important that prior assumptions about the influence of VNS on particular aspects of brain function do not constrain the investigations.

5-HT6 receptor antagonists improve performance in an attentional set shifting task in rats.

RATIONALE AND OBJECTIVE: Performance on the Wisconsin Card Sorting Test (WCST), which requires patients to 'shift attention' between stimulus dimensions (sorting categories), is impaired in diseases such as schizophrenia. The rat attentional set shifting task is an analogue of the WCST. Given that 5-HT(6) receptor antagonists improve cognitive performance and influence cortical neurochemistry in rats, the present study investigated the effects of 5-HT(6) receptor antagonists upon attentional set shifting in rats. METHODS: Rats were tested in this paradigm following sub-chronic SB-399885-T or SB-271046-A (both 10 mg kg(-1) bid, p.o. for 8 days prior to testing and either 4 or 2 h prior to testing on day 9, respectively). Rats were trained to dig in baited bowls for a food reward and to discriminate based on odour or digging media (Habituation, day 8). In a single session (day 9), rats performed a series of discriminations, including reversals (REV), intra-dimensional (ID) and extra-dimensional (ED) shifts. RESULTS: Neither compound altered performance during Habituation. On the test day, both SB-399885-T and SB-271046-A reduced the total trials to reach criterion and the total errors made when data were collapsed across all discriminations (P<0.05-0.01). Further, both compounds significantly reduced the trials to criterion for REV-1 (P<0.05-0.01) and abolished the ID/ED shift. SB-399885-T, but not SB-271046-A, reduced trials required to complete the ED shift (P<0.05) and the number of errors made during completion of the ID (P<0.05) and ED shifts (P<0.01). CONCLUSION: 5-HT(6) receptor antagonists improved performance in the attentional set shifting task and may have therapeutic potential in the treatment of disorders where cognitive deficits are a feature, including schizophrenia.

Recordings from the rat locus coeruleus during acute vagal nerve stimulation in the anaesthetised rat.

Vagal nerve stimulation (VNS) is used as a treatment for Epilepsy and is currently under investigation as a treatment for depression (see [M.S. George, Z. Nahas, X. Li, F.A. Kozel, B. Anderson, K. Yamanaka, J.H. Chae, M.J. Foust, Novel treatments of mood disorders based on brain circuitry (ECT, MST, TMS, VNS, DBS), Semin. Clin. Neuropsychiatry 7 (2002) 293-304; M.S. George, A.J. Rush, H.A. Sackeim, L.B. Marangell, Vagus nerve stimulation (VNS): utility in neuropsychiatric disorders, Int. J. Neuropsychopharmacol. 6 (2003) 73-83] for reviews). The mechanism of action of VNS is not fully understood [E. Ben-Menachem, Vagus-nerve stimulation for the treatment of epilepsy, Lancet Neurol. 1 (2002) 477-482] despite numerous imaging investigations (see [E. Ben-Menachem, Vagus-nerve stimulation for the treatment of epilepsy, Lancet Neurol. 1 (2002) 477-482; M.S. George, Z. Nahas, X. Li, F.A. Kozel, B. Anderson, K. Yamanaka, J.H. Chae, M.J. Foust, Novel treatments of mood disorders based on brain circuitry (ECT, MST, TMS, VNS, DBS), Semin. Clin. Neuropsychiatry 7 (2002) 293-304; M.S. George, A.J. Rush, H.A. Sackeim, L.B. Marangell, Vagus nerve stimulation (VNS): utility in neuropsychiatric disorders, Int J Neuropsychopharmacol 6 (2003) 73-83; M.S. George, H.A. Sackeim, L.B. Marangell, M.M. Husain, Z. Nahas, S.H. Lisanby, J.C. Ballenger, A.J. Rush, Vagus nerve stimulation. A potential therapy for resistant depression? Psychiatr. Clin. North Am. 23 (2000) 757-783] for reviews). However, there is some evidence to suggest that the locus coeruleus may play a role modulating the effects of VNS. This study investigated the effects of VNS (0.3mA), of sufficient intensity to recruit the A and B fibre components of the vagus [D.M. Woodbury, J.W. Woodbury, Effects of vagal stimulation on experimentally induced seizures in rats, Epilepsia 31 (Suppl. 2) (1990) S7-S19], on the discharge rate of single neurons from the locus coeruleus. This study is the first to demonstrate a direct neuronal response from the locus coeruleus following acute challenge of VNS in the anaesthetised rat. The results of this study indicate that neuronal activity of the locus coeruleus is modulated by VNS. This pathway through the locus coeruleus may be significant for mediating the clinical effects of VNS.

The thalamic reticular nucleus: more than a sensory nucleus?

Sensory information is routed to the cortex via the thalamus, but despite this sensory bombardment, animals must attend selectively to stimuli that signal danger or opportunity. Sensory input must be filtered, allowing only behaviorally relevant information to capture limited attentional resources. Located between the thalamus and cortex is a thin lamina of neurons called the thalamic reticular nucleus (Rt). The thalamic reticular nucleus projects exclusively to thalamus, thus forming an essential component of the circuitry mediating sensory transmission. This article presents evidence supporting a role for Rt beyond the mere relay of sensory information. Rather than operating as a component of the sensory relay, the authors suggest that Rt represents an inhibitory interface or "attentional gate," which regulates the flow of information between the thalamus and cortex. Recent findings have also implicated Rt in higher cognitive functions, including learning, memory, and spatial cognition. Drawing from recent insights into the dynamic nature of the thalamic relay in awake, behaving animals, the authors present a speculative account of how Rt might regulate thalamocortical transmission and ultimately the contents of consciousness.