Verity J. Brown

Orbital prefrontal cortex mediates reversal learning and not attentional set shifting in the rat

It has been demonstrated previously that lesions to medial prefrontal cortex in rats impair the shifting of attentional set between perceptual features of complex stimuli [J. Neurosci. 20 (2000) 4320], a result that mirrors the deficit found in humans and monkeys [Nature 380 (1996) 69; Behav. Neurosci. 110 (1996) 872; J. Neurosci. 17 (1997) 9285; Neuropsychologia 29 (1991) 993]. These data imply functional homology between rat medial prefrontal cortex and primate prefrontal cortex.In marmoset monkeys, there is a double dissociation between the effects of lesions of lateral prefrontal cortex, which impair shifting of attentional set, and lesions of orbital prefrontal cortex, which result in impairments of reversal of stimulus-reward contingencies, leaving attentional set-shifting capacities intact [Nature 380 (1996) 69; Behav. Neurosci. 110 (1996) 872; J. Neurosci. 17 (1997) 9285]. The present investigation examined whether lesions to rat orbital prefrontal cortex would produce deficits in reversal learning in the absence of deficits in shifting attentional set, as seen in monkeys. Rats were trained to perform an attentional set-shifting task that is formally the same as that used in monkeys and humans. In a single session, rats performed a series of discriminations, including acquisitions and reversals. Damage to orbital prefrontal cortex in the rats did not disrupt the ability to acquire, maintain or shift attentional set. We report here the same selective impairment in reversal learning in rats as seen in primates with orbital prefrontal cortex lesions.

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 Alzheimers 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.

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.

Lesions of the dorsal noradrenergic bundle impair attentional set‐shifting in the rat

Rats with medial prefrontal cortex (mPFC) lesions are impaired in attentional set‐shifting, when it is required to shift to a previously irrelevant perceptual dimension. The main source of noradrenergic input to the mPFC is from the locus coeruleus via the dorsal noradrenergic ascending bundle (DNAB). This study examined the effects of selective cortical noradrenaline depletion following 6‐hydroxydopamine‐induced lesions of the DNAB on attentional set‐shifting and other aspects of discrimination learning and performance. Rats learned to dig in baited bowls, and then acquired discriminations based on one of two aspects of a bowl − odour or digging medium. The task tested acquisition of novel discriminations (both intra‐ and extra‐dimensional) and reversal learning when contingencies were reversed with the same stimuli. At the conclusion of testing, the DNAB‐lesioned rats were shown to have a selective depletion of noradrenaline of ∼ 70% within the mPFC (cingulate and prelimbic cortex subregions), with no other significant changes in dopamine or 5‐hydroxytryptamine. Rats required more trials to learn new discriminations when attentional shifting was required [extra‐dimensional (ED)‐shift]. Rats with dorsal noradrenergic ascending bundle (DNAB) lesions were impaired in novel acquisitions when an ED‐shift was required, but were unimpaired in reversal learning and other aspects of discrimination learning, relative to controls. These data are consistent with other evidence implicating noradrenaline (NA) in attentional set‐shifting, and contrast with effects of manipulations of 5‐hydroxytryptamine (5‐HT) and acetylcholine within the medial prefrontal cortex (mPFC). The findings are also relevant to recent theorizing about the functions of the coeruleo‐cortical noradrenergic system.

Double dissociation of social and environmental stimulation on spatial learning and reversal learning in rats

Environmental enrichment induces structural and biochemical changes in the brains of mammals that correlate with improved learning and memory. Research in rats suggests that social compared to inanimate stimulation might affect behavior differently, by acting upon dissociable neural substrates. Here we tested this hypothesis at the behavioral level by examining whether social and inanimate stimulation affect spatial memory formation and non-spatial discrimination reversal learning selectively. Spatial memory formation is known to depend on hippocampal-neocortical pathways, whereas reversal learning depends primarily on prefrontal cortico-striatal pathways. Male Lister hooded rats were housed singly or in groups of three in either small barren or large enriched cages, from weaning onwards. After 10 weeks of differential housing, spatial learning and memory were examined in the Morris water maze, followed by a series of tactile and odour discriminations, including discrimination reversal, in a two-choice discrimination task. Regardless of inanimate stimulation, social deprivation affected neither the acquisition of simple or complex discriminations, nor spatial memory formation, but was associated with impaired reversal learning in the two-choice discrimination task. By contrast, inanimate deprivation, regardless of social stimulation, affected neither acquisition nor reversal of two-choice discriminations, but selectively delayed the acquisition of spatial memory in the Morris water maze. This is the first demonstration of a double dissociation of early social and inanimate stimulation on two distinct behavioural functions that are mediated by dissociable underlying neural pathways. These findings strengthen the view that social and inanimate stimulation act, at least in part, upon dissociable neural substrates.

Reaction Time Deficits and Parkinson's Disease

Controversy surrounds the existence and nature of reaction time deficits in Parkinsons disease. Three areas of research are reviewed: the use of precues to speed movement (motor preprogramming), the effects of medication on reaction time, and simple reaction times. No evidence is found for a motor preprogramming deficit, and the presence of a parkinsonian reaction time deficit after medication withdrawal is found to be dependent upon experimental design and the withdrawal method used. Parkinsons disease is found to cause a consistent deficit in simple reaction time. A quantitative analysis of past studies reveals that a parkinsonian reaction time deficit is more likely to be present in tasks that controls can perform with a fast reaction time. This relationship between deficit and control group reaction time applies to choice, but not simple, reaction time tasks. Many studies compare patient and control choice reaction times across experimental conditions that cause control reaction time to vary. The authors of these studies should consider whether their results can be explained in terms of the simple relationship between patient reaction time deficit and control reaction time before drawing more complex conclusions from their data.

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.

Cholinergic neurotransmission influences covert orientation of visuospatial attention in the rat.

Abstract. Rationale: Both monkey and human studies have suggested that attentional orienting may be mediated by the cholinergic neurotransmitter system. Objectives: The purpose of the present study was to examine whether the cholinergic agonist (nicotine) and/or antagonist (scopolamine) influence covert orientation in the rat. Methods: Rats carried out a visual reaction time task to measure covert orienting of attention following systemic administration of nicotine or scopolamine. Results: Nicotine reduced reaction times, abolishing the validity effect by differentially speeding the reaction times for invalidly cued targets. Conversely, scopolamine increased the validity effect by disproportionately lengthening reaction times to invalidly cued targets. Conclusions: Taken together, these data indicate that cholinergic transmission represents an important neurochemical substrate of visuospatial attention, specifically influencing disengagement or movement of attention.

The effect of striatal dopamine depletion and the adenosine A2A antagonist KW-6002 on reversal learning in rats

This study assessed whether dopamine in the dorsomedial striatum is necessary for flexible adaptation to changes in stimulus-response contingencies. As KW-6002 (Istradefylline), an adenosine A(2A) antagonist, improves motor deficits resulting from striatal dopamine depletion, we also tested for potential ameliorative effects of KW-6002 on dopamine depletion-induced cognitive deficits. Male Lister hooded rats were presented with two bowls, discriminable by either a textured covering on the outer surface, their scent or the bowl contents (digging media) in which bait was buried. Once they had learned in which bowl food was buried, the stimulus-response contingencies were reversed. In both phases (acquisition and reversal), the criterion for learning was defined a priori as six consecutive correct trials. Following depletion of dopamine in the dorsomedial striatum, acquisition of the discriminations was intact but there was an increase in the number of trials to attain criterion performance in the reversal phases, indicating an impairment in reversal learning. KW-6002 (1mg/kg bidaily for 10 days) non-specifically increased the number of trials to criterion at all stages of the test and in both controls (sham-operated) and dopamine-depleted rats. Chronic KW-6002 treatment did not improve the reversal deficits in dopamine-depleted rats. These findings suggest that dopamine transmission in the dorsomedial striatum is critical for the flexible shifting of response patterns and the ameliorative effects of KW-6002 following depletion of dopamine in the striatum may be restricted to motor functions without relieving deficits in response-shifting flexibility.

The Efficacy of Policy Statements on Plagiarism: Do They Change Students' Views?

Concern about academic dishonesty has led to studies designed to explore its nature, prevalence, and causes. Nevertheless, to date there has been little empirical work designed to test the efficacy of measures to reduce cheating behavior. Many authors agree that there should be institutional statements about academic dishonesty that give definitions and state the penalties for cheating. The purpose of this study was to examine the efficacy of such statements in terms of their influence on perceived severity and perceived incidence of plagiarism in undergraduates. We found that having the students read a carefully worded statement about plagiarism was an effective way to change the perceptions of how seriously plagiarism breaches academic guidelines. Our data further suggest that providing guidance about avoiding plagiarism that encourages students to take a more serious view of the issue is likely to have positive effects on future behavior.