Neonatal ventral hippocampus lesions disrupt extra-dimensional shift and alter dendritic spine density in the medial prefrontal cortex of juvenile rats

Recent data showed that neonatal ventral hippocampus (VH) lesions, an approach used to model schizophrenia symptoms in rodents, produce premature deficits of working memory believed to be associated with early medial prefrontal cortex (mPFC) maldevelopment. This experiment expands the investigation of mPFC integrity in juvenile rats with neonatal VH lesions by assessing behavioral flexibility and dendritic spine density. Sixteen Sprague-Dawley male pups received bilateral microinjections of ibotenic acid in the VH or SHAM surgery on postnatal day (PND) 6. On PND 29 and 30, rats were subjected to a spatial shift task in a cross-maze; an attentional set-shifting task was then administered on two consecutive days, between PND 33 and PND 35. Rats were sacrificed at PND 36 and dendritic spine density in the mPFC was assessed using Golgi-Cox staining procedure. Results revealed impaired extra-dimensional shift in VH-lesioned rats and inconsistent reversal discrimination outcomes. Although lesioned animals displayed intact performance in the spatial shift, rates of perseverative responses were higher than normal in this task. Neonatal VH damage resulted in lower dendritic spine density in the mPFC than measured in control brains; however, no significant correlation was found between this outcome and behavioral data. Juvenile morphological and cognitive perturbations are consistent with the early emergence of mPFC anomalies following neonatal VH lesions. Results are discussed in relation with potential common mechanisms linking pre- and post-pubertal onsets of behavioral dysfunction.     

Layer and regional effects of environmental enrichment on the pyramidal neuron morphology of the rat

The environmental enrichment (EE) paradigm is widely used to study experience-dependent brain plasticity. Several studies have investigated functional and anatomical EE effects. However, as EE effects are different according to cerebral region, cortical layer, dendritic field and morphological index considered, a univocal characterization of neuronal morphological changes following rearing in enriched environments is lacking.Aim of the present study was to characterize in the rat the effects of EE on the neuronal morphology of frontal and parietal cortical regions, the main target areas of the stimulation provided by the paradigm. Male Wistar rats were housed in an enriched environment for 3.5 months from the 21st postnatal day. For the morphological analysis, biotinylated dextran amine (BDA)-labeled pyramidal neurons were selected from frontal (M1–M2) and parietal (S1–S2) cortical layers III and V. Apical and basal dendritic branching and spines were analyzed using the Sholl method.Results showed that EE increased branching and spines in both layers of frontal cortex, but had a greater effect on apical arborization. In parietal cortex, EE significantly affected branching and spines in layer III but not layer V neurons, in which only a tendency to be influenced by the rearing conditions was observed in basal arborization.It is hypothesized that these multifaceted morphological EE effects are connected to the heavy involvement of a sensory-motor circuit engaged in the guidance of voluntary action and in motor learning activated by EE stimulation.     

Inhibition and the right inferior frontal cortex

It is controversial whether different cognitive functions can be mapped to discrete regions of the prefrontal cortex (PFC). The localisationist tradition has associated one cognitive function - inhibition - by turns with dorsolateral prefrontal cortex (DLPFC), inferior frontal cortex (IFC), or orbital frontal cortex (OFC). Inhibition is postulated to be a mechanism by which PFC exerts its effects on subcortical and posterior-cortical regions to implement executive control. We review evidence concerning inhibition of responses and task-sets. Whereas neuroimaging implicates diverse PFC foci, advances in human lesion-mapping support the functional localization of such inhibition to right IFC alone. Future research should investigate the generality of this proposed inhibitory function to other task domains, and its interaction within a wider network.     

Planning and problem solving skills following focal frontal brain lesions in childhood: analysis using the Tower of London.

Problem solving skills were investigated in children with focal lesions using the Tower of London test (TOL; Shallice, 1982). The scoring procedure was elaborated from previous studies to delineate separate processes contributing to overall performance in children. Thirty-one children with focal frontal pathology, 18 children with focal pathology in other brain regions (extra-frontal), 17 children with generalized pathology and 38 healthy children participated in the study. Results suggest a distributed network for problem solving skills, particularly cognitive flexibility and goal setting skills. Within the frontal group, children with lesions involving the right pre-frontal cortex had greatest problems with self-regulation, with rule breaks most common among this group. As these skills develop relatively early in comparison to other aspects of executive function, right pre-frontal regions may play a particularly important role in the development of executive skills in childhood, with damage to these regions rendering children vulnerable to a range of cognitive and social deficits.     

Planning and Problem Solving Skills Following Focal Frontal Brain Lesions in Childhood: Analysis Using the Tower of London

Problem solving skills were investigated in children with focal lesions using the Tower of London test (TOL; Shallice, 1982). The scoring procedure was elaborated from previous studies to delineate separate processes contributing to overall performance in children. Thirty-one children with focal frontal pathology, 18 children with focal pathology in other brain regions (extra-frontal), 17 children with generalized pathology and 38 healthy children participated in the study. Results suggest a distributed network for problem solving skills, particularly cognitive flexibility and goal setting skills. Within the frontal group, children with lesions involving the right pre-frontal cortex had greatest problems with self-regulation, with rule breaks most common among this group. As these skills develop relatively early in comparison to other aspects of executive function, right pre-frontal regions may play a particularly important role in the development of executive skills in childhood, with damage to these regions rendering children vulnerable to a range of cognitive and social deficits.     

Fetal alcohol syndrome and the developing socio-emotional brain

Fetal alcohol syndrome (FAS) is currently recognized as the most common known cause of mental retardation, affecting from 1 to 7 per 1000 live-born infants. Individuals with FAS suffer from changes in brain structure, cognitive impairments, and behavior problems. Researchers investigating neuropsychological functioning have identified deficits in learning, memory, executive functioning, hyperactivity, impulsivity, and poor communication and social skills in individuals with FAS and fetal alcohol effects (FAE). Investigators using autopsy and brain imaging methods have identified microcephaly and structural abnormalities in various regions of the brain (including the basal ganglia, corpus callosum, cerebellum, and hippocampus) that may account for the neuropsychological deficits. Results of studies using newer brain imaging and analytic techniques have indicated specific alterations (i.e., displacements in the corpus callosum, increased gray matter density in the perisylvian regions, altered gray matter asymmetry, and disproportionate reductions in the frontal lobes) in the brains of individuals prenatally exposed to alcohol, and their relations with brain function. Future research, including using animal models, could help inform our knowledge of brain-behavior relations in the context of prenatal alcohol exposure, and assist with early identification and intervention.     

Subtle cognitive deficits in severe alcohol addicts – Do they show a specific profile?

Although alcohol dependency is a burden to society, data on cognitive performance in therapy‐resistant patients after multiple withdrawals are poor. In this study, 22 patients without reported cognitive deficits and 20 control subjects performed extensive cognitive testing and a motor task assessing short‐term memory. Patients displayed subtle deficits (mainly in executive function), while memory functions were relatively unimpaired. Our results suggest that subtle frontal‐executive deficits may contribute to a poor prognosis, but could be missed by routine clinical tests.     

The contribution of distinct subregions of the ventromedial frontal cortex to emotion,social behavior,and decision making

Damage to the ventromedial frontal cortex (VMFC) in humans is associated with deficits in decision making. Decision making, however, often happens while people are interacting with others, where it is important to take the social consequences of a course of action into account. It is well known that VMFC lesions also lead to marked alterations in patients’ emotions and ability to interact socially; however, it has not been clear which parts of the VMFC are critical for these changes. Recently, there has been considerable interest in the role of the VMFC in choice behavior during interpersonal exchanges. Here, we highlight recent research that suggests that two areas within or adjacent to the VMFC, the orbitofrontal cortex (OFC) and the anterior cingulate cortex (ACC), may play distinct but complementary roles in mediating normal patterns of emotion and social behavior. Converging lines of evidence from human, macaque, and rat studies now suggest that the OFC may be more specialized for simple emotional responses, such as fear and aggression, through its role in representing primary reinforcement or punishment. By contrast, the ACC may play a distinct role in more complex aspects of emotion, such as social interaction, by virtue of its connections with the discrete parts of the temporal lobe and subcortical structures that control autonomic responses.     

Encoding and retrieval are differentially processed by the anterior cingulate and prelimbic cortices: A study based on trace eyeblink conditioning in the rabbit

A growing body of literature suggests that structures along the midline of the prefrontal cortex (mPFC), including Brodmann’s area 32 (prelimbic cortex) and area 24 (anterior cingulate cortex) in the rabbit play a role in retrieval of learned information. The present studies compared the effects of post-training lesions produced either immediately or 1-week following learning, to either prelimbic (area 32) or anterior cingulate (area 24) cortex on trace eyeblink (EB) conditioning. Further, because recent evidence suggests that the mPFC may play an even greater role in learning and memory when emotional arousal is low, these studies compared the effects of lesions in groups conditioned with either a relatively low-arousal corneal airpuff, or a more aversive periorbital eyeshock unconditioned stimulus (US). A total of six groups were tested, which received selective ibotenic acid or “sham” control lesions to either area 32 or 24, immediately or 1-week following asymptotic learning, and conditioned with an eyeshock US or an airpuff US. Results showed that the greatest lesion deficits were found when conditioning with the less aversive airpuff US. Further, lesions produced to area 32 one-week, but not immediately following learning, caused significant deficits in performance, while lesions produced to area 24 immediately, but not 1-week following learning, caused significant deficits in performance. These findings add to the body of evidence which shows that area 32 of the mPFC regulates retrieval, but not acquisition or storage of information, while area 24 mediates a less specific reacquisition process, but not permanent storage or retrieval of information during relearning of memories abolished by mPFC damage. These findings were, however, specific to those experiments in which the relatively non-aversive airpuff was the US.     

Theory of Mind in Patients with Epilepsy: a Systematic Review and Meta-analysis

The ability to understand our own thoughts, intentions, beliefs and emotions and those of others (Theory of Mind; ToM) is a high-order social cognitive skill that is vital for social interaction and which has been found to be impaired in patients with epilepsy. Studies examining ToM in patients with epilepsy, however, have yielded inconsistent findings. The main aim of this study is to determine whether the magnitude of ToM deficits varies as a function of the site of epilepsy focus and/or the type of ToM task used. Electronic databases searches included Psychinfo, Medline/PubMed and EMBASE. Studies were included if they examined a group of patients with epilepsy and a group of healthy controls, reported original research, were published in the English language in peer reviewed journals, and used one of five empirically validated measures of ToM: False Belief, Reading the Mind in the Eyes Task (RMET), Faux-pas, Strange Stories, Cartoon ToM vignettes. Twelve studies were identified, ten included adults and two included children with epilepsy. Findings revealed marked ToM deficits in adults with focal seizures emanating from core brain regions underpinning ToM: temporal and frontal lobes (frontal lobe epilepsy, FLE; temporal lobe epilepsy, TLE), but not in adults with focal seizures outside the temporal and frontal lobes (extra-TLE/FLE). ToM deficits were also observed in children with generalised seizures (idiopathic generalised epilepsy, IGE). ToM deficits were documented across ToM tasks. In conclusion, ToM deficits represent a robust finding in adults with frontal and temporal epilepsy, but are also found in children with generalised seizures. Further research into ToM is needed, especially in children with epilepsy as early ToM may have cumulative, negative effects on development of social skills that continues into adulthood.     

Semantic encoding deficits in a case of traumatic amnesia

A 33-year-old patient was studied neuropsychologically 19 years after sustaining severe head trauma. A recent CT scan showed lesions in the left frontal and right temporal regions. Performance on standard memory tests, both verbal and visuospatial, was extremely poor, although other intellectual functioning was relatively spared. The patient showed some interesting deficits in semantic processing. In a depth of processing task there was no advantage for words where semantic encoding had been induced. Neither was there any release from proactive interference after shifts in semantic categories. Deficits were also observed in short-term memory distractor tasks as well as in cueing tasks. These findings suggest that the cognitive deficits commonly observed in Korsakoff's disease can also be present in other amnesic disorders and may in part be related to cortical and especially frontal lobe atrophy.     

The impact of lesion laterality on neuropsychological change following posterior pallidotomy: a review of current findings

This paper reviews seven studies evaluating the impact of lesion laterality on the neuropsychological sequelae of posterior pallidotomy for treatment of Parkinson's disease. Left lesions of the internal globus pallidus (GPi) were associated with subtle deficits on measures sensitive to frontal lobe function. The findings of a randomized clinical trial including a patient control group indicated that many of these deficits were transient, resolving by 6 months following surgery. Right GPi lesions were not consistently associated with neuropsychological deficit, except in one study that included a significant proportion of demented patients. It is hypothesized that when neuropsychological decline is present following surgery, this reflects impingement of posterior GPi lesions into proximal regions such as anterior GPi or the external pallidum that participate in cognitive basal ganglia-thalamocortical circuits. The findings from neuroimaging will be important for elucidating the relationship between lesion locus and neuropsychological sequelae.     

Laminar-dependent dendritic spine alterations in the motor cortex of adult rats following callosal transection and forced forelimb use

Previously, the authors found that partial denervation of the motor cortex in adult animals can enhance this region's neuronal growth response to relevant behavioral change. Rats with partial corpus callosum transections that were forced to rely on one forelimb for 18 days had increased dendritic arborization of layer V pyramidal neurons in the opposite motor cortex compared to controls. This was not found as a result of denervation alone or of forced forelimb use alone. However, it seemed possible that each independent manipulation (i.e., forced forelimb use alone and callosal transections alone) resulted in neural structural alterations that were simply not revealed in measurements of dendritic branch number and/or not inclusive of layer V dendrites. This possibility was assessed in the current study with a reexamination of the Golgi-Cox impregnated tissue generated in the previous study. Tissue was quantified from rats that received either partial transections of the rostral two-thirds of the corpus callosum (CCX) or sham operations (Sham) followed either by 18 days of forced use of one forelimb (Use) or unrestricted use of both forelimbs (Cont). Measurements of apical and basilar dendrites from pyramidal neurons of layer II/III and layer V were performed to detect spine addition resulting from either increased spine density or the addition of dendritic material. As hypothesized, significant spine addition was found following forced forelimb use alone (Sham+Use) and callosal transections alone (CCX+Cont). However, forced use primarily increased spines on layer II/III pyramidal neurons, whereas callosal transections primarily increased dendritic spines on layer V pyramidal neurons in comparison to Sham+Cont. A much more robust increase in layer V dendritic spines was found in animals with the combination of forced forelimb use and denervation (CCX+Use). In contrast to the effects of forced use alone, however, CCX+Use rats failed to show major net increases in spines on layer II/III neurons. These results indicate that while callosal denervation may greatly enhance the neuronal growth and synaptogenic response to behavioral change in layer V, it may also limit spine addition associated with forced forelimb use in layer II/III of the motor cortex.     

Prefrontal and hippocampal contributions to encoding and retrieval of spatial memory

The prefrontal cortex is thought to be critical for goal-directed action and the hippocampus is known to be importantly involved in spatial memory. Several studies have been suggestive of a role for the orbitofrontal cortex (OFC) in spatial navigation. However, the medial prefrontal cortex (mPFC) receives projections directly from the intermediate CA1 (iCA1) region of hippocampus and this link may be critical for spatial navigation. The purpose of the present investigation was to test the performance of rats receiving bilateral or disconnection infusions of lidocaine into OFC, mPFC, or iCA1 to determine the contribution of these structures to encoding and retrieval of spatial memory using the Hebb–Williams maze. A total of 92 male Long-Evans rats received chronic bilateral, contralateral, or ipsilateral implantation of cannulas into OFC, mPFC, or iCA1. Prior to testing on day 1 or day 2, subjects received central infusions of saline or lidocaine. The number of errors committed on the first five trials compared to the second five trials of day 1 was used to determine encoding, whereas retrieval was determined by comparing the second five trials of day 1 with the first five trials of day 2. The present findings suggest that mPFC and iCA1 are necessary and interact during encoding and retrieval; however, the OFC does not appear to be essential for either process. While the nature of the interaction between mPFC and iCA1 during encoding and retrieval is unclear, it may be supported by the integration of goals and spatial cues or strategy switching.     

认知判断中手部动作模拟的fMRI研究

该研究采用功能磁共振成像技术,考察不同条件下进行工具认知判断时手部姿势对认知判断的影响及动作模拟的神经机制。实验发现：手部姿势存在显著的主效应,冲突手部姿势条件下反应时最慢,且冲突手部姿势条件下与不冲突手部姿势条件下、自然状态条件下反应时存在显著差异,自然状态条件与不冲突手部姿势条件下反应时不存在显著差异。另外,f MRI成像结果发现,额中回、额下回、顶下小叶以及辅助运动区在自然状态下有显著激活,表明个体在进行认知判断过程中有动作模拟过程;海马结构、扣带回及楔前叶等与记忆有关的脑区有显著激活,表明身体经验在认知过程的作用。总的研究表明,不同的手部姿势状态对认知判断有不同影响,冲突手部姿势会对动作模拟产生干扰作用,手部动作模拟的神经机制主要涉及镜像神经元区,且在认知判断时存在具身效应。     

Contrasting effects of motor and visual spatial learning tasks on dendritic arborization and spine density in rats

Rats were trained in four different learning tasks including the Morris-water task, a T-maze delayed nonmatch-to-sample task, a skilled unilateral reaching task, and a skilled bilateral string-pulling task. At the end of training the brains were harvested and stained using a Golgi-Cox procedure. Learning the spatial navigation task produced increased dendritic length and branching as well as decreased spine density in layer III pyramidal cells in occipital cortex. Learning the T-maze task increased dendritic branching in layer III medial but not orbital frontal cortex pyramidal cells and increased spine density in both regions. The motor learning tasks produced increased dendritic length and branching in layer V pyramidal cells in the forelimb cortex in the hemisphere contralateral to the trained limb in the unilateral skilled reaching task and in both limbs in the bilateral skilled pulling task. There were no changes in spine density in layer V in the motor tasks, but there was a decrease in spine density in layer III in the unilateral reaching task. Spatial and motor learning thus produce different patterns of change in layer III cortical pyramidal neurons. Furthermore, changes in spine density and dendritic length and branching are not tightly correlated and can increase and/or decrease independently of one another in learning tasks.     

Cerebellar dentate nuclei lesions reduce motivation in appetitive operant conditioning and open field exploration

Recently identified pathways from the dentate nuclei of the cerebellum to the rostral cerebral cortex via the thalamus suggest a cerebellar role in frontal and prefrontal non-motor functioning. Disturbance of cerebellar morphology and connectivity, particularly involving these cerebellothalamocortical (CTC) projections, has been implicated in motivational and cognitive deficits. The current study explored the effects of CTC disruption on motivation in male Long Evans rats. The results of two experiments demonstrate that electrolytic lesions of the cerebellar dentate nuclei lower breaking points on an operant conditioning progressive ratio schedule and decrease open field exploration compared to sham controls. Changes occurred in the absence of motor impairment, assessed via lever pressing frequency and rotarod performance. Similar elevated plus maze performances between lesioned and sham animals indicated that anxiety did not influence task performance. Our results demonstrate hedonic and purposive motivational reduction and suggest a CTC role in global motivational processes. These implications are discussed in terms of psychiatric disorders such as schizophrenia and autism, in which cerebellar damage and motivational deficits often present concomitantly.     

Lesions of orbitofrontal cortex and basolateral amygdala complex disrupt acquisition of odor-guided discriminations and reversals

Recent work indicates that both orbitofrontal cortex (OFC) and the basolateral complex of the amygdala (ABL) are involved in processes by which cues are associated with predicted outcomes. To examine the respective roles of these structures in discrimination learning, rats with bilateral sham or neurotoxic lesions of either OFC or ABL were trained on a series of four 2-odor discrimination problems in a thirst-motivated go, no-go task. After acquisition of the series of odor problems, the rats were trained on serial reversals of the final odor problem. Performance on each problem was assessed by monitoring accuracy of choice behavior, and also by measuring latency to respond for fluid outcomes after odor sampling. During discrimination learning, rats in both lesioned groups had similar deficits, failing to show normal changes in response latency during learning, while at the same time exhibiting normal choice behavior relative to controls. Choice behavior was affected only during the reversal phase of training, in which OFC and ABL lesions produced distinctive deficits. Rats with ABL lesions were impaired on the first reversal (S1−/S2+), but were unimpaired at acquiring a reversal back to the original odor-outcome contigencies (S1+/S2−), whereas rats with OFC lesions were impaired on both types of reversals. These findings suggest that OFC and ABL serve partially overlapping roles in the use of incentive information that supports normal discrimination performance.     

Frontal lobe dysfunction and everyday problem-solving: social and non-social contributions

Everyday problem-solving involves both non-social executive processes, social and emotional processes, and draws upon social and practical knowledge. A series of studies including both adult-acquired lesions and neurodevelopmental disorders is reviewed examining problem-solving on a real-life-type task that involves generating a range of solutions to brief problem scenarios and selecting preferred solutions to solve the problems. Impairments in problem-solving are described in groups of participants with left anterior frontal lobe lesions, Tourette's syndrome and Asperger's syndrome. By contrast, healthy older people did not show problem-solving deficits on the same task. The possible contributions of non-social executive skills, social and emotional skills, and knowledge acquired from experience are each considered in relation to everyday performance. Multiple cognitive/emotional routes to the development of everyday life difficulties pose a complex challenge both in understanding the nature of the relevant processes and in developing adequate methods for management and rehabilitation.