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1.  Multiple clinically-relevant hormone therapy regimens fail to improve cognitive function in aged ovariectomized rhesus monkeys 
Neurobiology of aging  2013;34(7):1882-1890.
Preclinical studies in aged, surgically-menopausal rhesus monkeys have revealed powerful benefits of intermittent estrogen injections on prefrontal cortex-dependent working memory, together with corresponding effects on dendritic spine morphology in the prefrontal cortex. This contrasts with the inconsistent effects of hormone therapy (HT) reported in clinical studies in women. Factors contributing to this discrepancy could include differences in the formulation and sequence of HT regimens, resulting in different neurobiological outcomes. The current study evaluated, in aging surgically menopausal rhesus monkeys, the cognitive effects of four HT regimens modeled directly on human clinical practice, including continuous estrogen treatment opposed by progesterone. None of the regimens tested produced any cognitive effect, despite yielding physiologically relevant serum hormone levels, as intended. These findings have implications for the design of regimens that might optimize the benefits of hormone treatment for healthy aging, and suggest that common HT protocols used by women may fail to result in substantial cognitive benefit, at least via direct effects on the prefrontal cortex.
doi:10.1016/j.neurobiolaging.2012.12.017
PMCID: PMC3622837  PMID: 23369546
ovarian hormones; aging; macaque; learning; memory; prefrontal; temporal
2.  Selective anesthesia-induced neuroinflammation in developing mouse brain and cognitive impairment 
Anesthesiology  2013;118(3):502-515.
Background
Recent population studies have suggested that children with multiple exposures to anesthesia and surgery at an early age are at an increased risk of cognitive impairment. We therefore have established an animal model with multiple versus single exposures of anesthetic(s) in young versus adult mice, aiming to distinguish the role of different anesthesia in cognitive impairment.
Methods
Six day and 60 day-old mice were exposed to various anesthesia regimen. We then determined the effects of the anesthesia on learning and memory function, levels of pro-inflammatory cytokine interleukin-6 and tumor necrosis factor-α in brain tissues, and the amount of ionized calcium binding adaptor molecule 1 positive cells, the marker of microglia activation, in the hippocampus.
Results
Here we show that anesthesia with 3% sevoflurane two hours daily for three days induced cognitive impairment and neuroinflammation [e.g., increased interleukin-6 levels: 151% ± 2.3 (mean ± SD) versus 100% ± 9.0, P = 0.035, n = 6] in young, but not adult, mice. Anesthesia with 3% sevoflurane two hours daily for one day and 9% desflurane two hours daily for three days induced neither cognitive impairment nor neuroinflammation. Finally, an enriched environment and anti-inflammation treatment (ketorolac) ameliorated the sevoflurane anesthesia-induced cognitive impairment.
Conclusions
Anesthesia-induced cognitive impairment may depend on developmental stage, anesthetic agent, and the number of exposures. These findings also suggest the cellular basis and the potential prevention and treatment strategies for the anesthesia-induced cognitive impairment, which may ultimately lead to safer anesthesia care and better postoperative outcomes for children.
doi:10.1097/ALN.0b013e3182834d77
PMCID: PMC3580002  PMID: 23314110
3.  Acetylcholine facilitates recovery of episodic memory after brain damage 
Episodic memory depends on a network of interconnected brain structures including the inferior temporal cortex, hippocampus, fornix and mammillary bodies. We have previously shown that a moderate episodic memory impairment in monkeys with transection of the fornix is exacerbated by prior depletion of acetylcholine from inferotemporal cortex. This is despite the fact that depletion of acetylcholine from inferotemporal cortex on its own has no effect on episodic memory. Here we now show that this effect occurs because inferotemporal acetylcholine facilitates recovery of function following structural damage within the neural circuit for episodic memory. Episodic memory impairment caused by lesions of the mammillary bodies, like fornix transection, was exacerbated by prior removal of temporal cortical acetylcholine. However, removing temporal cortical acetylcholine after the lesion of the fornix or mammillary bodies did not increase the severity of the impairment. This lesion order effect suggests that acetylcholine within the inferior temporal cortex ordinarily facilitates functional recovery after structural lesions that impair episodic memory. In the absence of acetylcholine innervation to inferotemporal cortex, this recovery is impaired and the amnesia caused by the structural lesion is more severe. These results suggest that humans with loss of cortical acetylcholine function, for example in Alzheimer’s disease, may be less able to adapt to memory impairments caused by structural neuronal damage to areas in the network important for episodic memory.
doi:10.1523/JNEUROSCI.2947-12.2012
PMCID: PMC3475489  PMID: 23035090
4.  Systemic Inflammation Impairs Attention and Cognitive Flexibility but Not Associative Learning in Aged Rats: Possible Implications for Delirium 
Delirium is a common and morbid condition in elderly hospitalized patients. Its pathophysiology is poorly understood but inflammation has been implicated based on a clinical association with systemic infection and surgery and preclinical data showing that systemic inflammation adversely affects hippocampus-dependent memory. However, clinical manifestations and imaging studies point to abnormalities not in the hippocampus but in cortical circuits. We therefore tested the hypothesis that systemic inflammation impairs prefrontal cortex function by assessing attention and executive function in aged animals. Aged (24-month-old) Fischer-344 rats received a single intraperitoneal injection of lipopolysaccharide (LPS; 50 μg/kg) or saline and were tested on the attentional set-shifting task (AST), an index of integrity of the prefrontal cortex, on days 1–3 post-injection. Plasma and frontal cortex concentrations of the cytokine TNFα and the chemokine CCL2 were measured by ELISA in separate groups of identically treated, age-matched rats. LPS selectively impaired reversal learning and attentional shifts without affecting discrimination learning in the AST, indicating a deficit in attention and cognitive flexibility but not learning globally. LPS increased plasma TNFα and CCL2 acutely but this resolved within 24–48 h. TNFα in the frontal cortex did not change whereas CCL2 increased nearly threefold 2 h after LPS but normalized by the time behavioral testing started 24 h later. Together, our data indicate that systemic inflammation selectively impairs attention and executive function in aged rodents and that the cognitive deficit is independent of concurrent changes in frontal cortical TNFα and CCL2. Because inattention is a prominent feature of clinical delirium, our data support a role for inflammation in the pathogenesis of this clinical syndrome and suggest this animal model could be useful for studying that relationship further.
doi:10.3389/fnagi.2014.00107
PMCID: PMC4050637  PMID: 24959140
aging neuroscience; rats; inflammation; frontal cortex; lipopolysaccharides; CCL2; set-shifting
5.  Mediodorsal thalamus and cognition in non-human primates 
Several recent studies in non-human primates have provided new insights into the role of the medial thalamus in different aspects of cognitive function. The mediodorsal nucleus of the thalamus (MD), by virtue of its connectivity with the frontal cortex, has been implicated in an array of cognitive functions. Rather than serving as an engine or relay for the prefrontal cortex, this area seems to be more specifically involved in regulating plasticity and flexibility of prefrontal-dependent cognitive functions. Focal damage to MD may also exacerbate the effects of damage to other subcortical relays. Thus, a wide range of distributed circuits and cognitive functions may be disrupted from focal damage within the medial thalamus (for example as a consequence of stroke or brain injury). Conversely, this region may make an interesting target for neuromodulation of cognitive function via deep brain stimulation or related methods, in conditions associated with dysfunction of these neural circuits.
doi:10.3389/fnsys.2013.00038
PMCID: PMC3734369  PMID: 23964206
thalamus; mediodorsal nucleus; retrograde amnesia; anterograde amnesia; hippocampus; prefrontal
6.  Prefrontal-temporal disconnection impairs recognition memory but not familiarity discrimination 
Neural mechanisms in the temporal lobe are essential for recognition memory. Evidence from human functional imaging and neuropsychology and monkey neurophysiology and neuropsychology also suggests a role for prefrontal cortex in recognition memory. To examine the interaction of these cortical regions in support of recognition memory we tested rhesus monkeys with prefrontal-inferotemporal (PFC-IT) cortical disconnection on two recognition memory tasks, a ‘Constant Negative’ task and delayed nonmatching-to-sample (DNMS). In the Constant Negative task monkeys were presented with sets of 100 discrimination problems. In each problem one unrewarded object was presented once every day, and became familiar over the course of several days testing. The other, rewarded object was always novel. In this task monkeys learned to avoid the familiar ‘constant negatives’ and choose the novel objects, so performance on this task is guided by a sense of familiarity for the constant negatives. Following PFC-IT disconnection monkeys were severely impaired at reacquiring the rule (to avoid familiar items) but were subsequently unimpaired at acquiring new constant negative problems, thus displaying intact familiarity recognition. The same monkeys were impaired in the acquisition of the DNMS task, as well as memory for lists of objects. This dissociation between two tests of recognition memory is best explained in terms of our general hypothesis that PFC-IT interactions support the representation of temporally complex events, which is necessary in DNMS but not in Constant Negative. These findings, furthermore, indicate that stimulus familiarity can be represented in the temporal cortex without input from the prefrontal cortex.
doi:10.1523/JNEUROSCI.5759-12.2013
PMCID: PMC3797511  PMID: 23739963
prefrontal; recognition memory; temporal cortex; novelty; object learning
7.  Cholinergic modulation of a specific memory function of prefrontal cortex 
Nature neuroscience  2011;14(12):1510-1512.
SUMMARY
Deficits in prefrontal cholinergic function are implicated in cognitive impairment in many neuropsychiatric diseases, but acetylcholine’s specific role remains elusive. Rhesus monkeys with selective lesions of cholinergic input to prefrontal cortex were unimpaired in tests of decision-making and episodic memory that require intact prefrontal cortex, but were severely impaired on a spatial working memory task. These observations are consistent with a specific role for prefrontal acetylcholine in working memory.
doi:10.1038/nn.2971
PMCID: PMC3432567  PMID: 22057191
cholinergic; prefrontal; dorsolateral; ventrolateral; orbital; frontal; spatial memory; episodic; decision-making; reward
8.  Long-Term Effects of Neonatal Single or Multiple Isoflurane Exposures on Spatial Memory in Rats 
General anesthetics are neurotoxic to neonatal rodents and non-human primates. Neonatal exposure to general anesthetics has been associated with long-term cognitive deficits in animal models. Some data from humans are consistent with long-term deleterious effects of anesthetic exposure early in life on cognitive development, with multiple exposures to general anesthetics being particularly damaging. We sought to determine whether repeated exposure of neonatal rats to anesthesia was associated with long-term cognitive impairments and whether the magnitude of impairments was greater than that resulting from a single exposure. Male or female Long–Evans rat pups were exposed to 1.8% isoflurane for 2 h on postnatal day (P) 7, or for 2 h each on P7, P10, and P13. Testing in a spatial working memory task began on P91. Rats that were repeatedly exposed to isoflurane were impaired relative to controls in the spatial working memory task. Male rats that received a single exposure to isoflurane showed an unexpected facilitation in spatial memory performance. These results support the hypothesis that multiple neonatal exposures to general anesthesia are associated with greater long-term cognitive impairment than a single exposure. The findings are congruent with human epidemiological studies reporting long-term cognitive impairments following multiple but not single general anesthetics early in life.
doi:10.3389/fneur.2013.00087
PMCID: PMC3703565  PMID: 23847588
pediatric anesthesia; anesthetic neurotoxicity; neurodevelopment; cognitive impairment; Hippocampus
9.  Sleep Deprivation in Rats Produces Attentional Impairments on a 5-Choice Serial Reaction Time Task 
Sleep  2006;29(1):69-76.
Study Objectives
To develop a rodent model of the attentional dysfunction caused by sleep loss.
Design
The attentional performance of rats was assessed after 4, 7, and 10 hours of total sleep deprivation on a 5-choice serial reaction time task, in which rats detect and respond to brief visual stimuli.
Setting
The rats were housed, sleep deprived, and behaviorally tested in a controlled laboratory setting.
Participants
Ten male Long-Evans rats were used in the study.
Interventions
Rats were trained to criteria and subsequently tested in daily sessions of 100 trials at approximately 4:00 pm (lights on 8:00 am-8:00 pm). Attentional performance was measured after 4, 7, 10 hours of total sleep deprivation induced by gentle handling.
Results
Sleep deprivation produced a monotonic increase in response latencies across the 4-hour, 7-hour, and 10-hour deprivations. Sleep deprivation also led to increased omission errors, but the overall number of perseverative and premature responses was unchanged. Subgroups of rats were differentially affected in the number of omission errors and perseverative responses.
Conclusions
The effects of sleep deprivation on rats are compatible with a range of human findings on the effects of sleepiness on selective attention, psychomotor vigilance, and behavioral control. Rats also exhibited differential susceptibility to the effects of sleep deprivation, consistent with ‘trait-like’ susceptibility that has been found in humans. These findings indicate the feasibility of using the 5-choice serial reaction time task as an animal model for investigating the direct links between homeostatic sleep mechanisms and resulting attentional impairments within a single animal subject.
PMCID: PMC3628810  PMID: 16453983
Sleep; total sleep deprivation; attention; rat; serial reaction time
10.  The Aging Cortical Synapse: Hallmarks and Implications for Cognitive Decline 
Nature reviews. Neuroscience  2012;13(4):240-250.
Normal aging is associated with impairments in cognitive function, including memory, and with specific and relatively subtle synaptic alterations in the hippocampus and prefrontal cortex. The authors describe these structural changes reported in monkeys and rodents, how they might affect age-associated cognitive decline and potential strategies to limit their impact.
doi:10.1038/nrn3200
PMCID: PMC3592200  PMID: 22395804
11.  Ventrolateral prefrontal cortex is required for performance of a strategy implementation task but not reinforcer devaluation effects in rhesus monkeys 
The European journal of neuroscience  2009;29(10):2049-2059.
The ability to apply behavioral strategies to obtain rewards efficiently and make choices based on changes in the value of rewards is fundamental to the adaptive control of behavior. The extent to which different regions of prefrontal cortex are required for specific kinds of decisions is not well-understood. We tested rhesus monkeys with bilateral ablations of ventrolateral prefrontal cortex on tasks that required the use of behavioral strategies to optimize the rate with which rewards were accumulated, or to modify choice behavior in response to changes in the value of particular rewards. Monkeys with ventrolateral prefrontal lesions were impaired in performing the strategy-based task, but not on value-based decision making. In contrast, orbital prefrontal ablations produced the opposite impairments in the same tasks. These findings support the conclusion that independent neural systems within the prefrontal cortex are necessary for control of choice behavior based on strategies or on stimulus value.
doi:10.1111/j.1460-9568.2009.06740.x
PMCID: PMC2688497  PMID: 19453635
macaque; monkey; prefrontal cortex; reward; reinforcement; rules
12.  Dorsolateral prefrontal lesions do not impair tests of scene learning and decision-making that require frontal-temporal interaction 
Theories of dorsolateral prefrontal cortex (DLPFC) involvement in cognitive function variously emphasize its involvement in rule implementation, cognitive control, or working and/or spatial memory. These theories predict broad effects of DLPFC lesions on tests of visual learning and memory. We evaluated the effects of DLPFC lesions (including both banks of the principal sulcus) in rhesus monkeys on tests of scene learning and strategy implementation that are severely impaired following crossed unilateral lesions of frontal cortex and inferotemporal cortex. Dorsolateral lesions had no effect on learning of new scene problems postoperatively, or on the implementation of preoperatively acquired strategies. They were also without effect on the ability to adjust choice behavior in response to a change in reinforcer value, a capacity that requires interaction between the amygdala and frontal lobe. These intact abilities following DLPFC damage support specialization of function within the prefrontal cortex, and suggest that many aspects of memory and strategic and goal-directed behavior can survive ablation of this structure.
doi:10.1111/j.1460-9568.2008.06353.x
PMCID: PMC2522287  PMID: 18702721
episodic; frontal cortex; macaque; memory; strategy
13.  Different behavioral effects of neurotoxic dorsal hippocampal lesions placed under either isoflurane or propofol anesthesia 
Hippocampus  2007;18(3):245-250.
Anesthetic protocols for behavioral neuroscience experiments are evolving as new anesthetics are developed and surgical procedures are refined to improve animal welfare. We tested whether neurotoxic dorsal hippocampal lesions produced under two different anesthetic protocols would have different behavioral and/or histo-pathological effects. Rats were anesthetized with either propofol, an intravenous anesthetic, or isoflurane, a gaseous anesthetic, and multiple injections of an excitotoxin (N-methyl-d-aspartate) were stereotaxically placed in the dorsal hippocampus bilaterally. Intraoperative physiological parameters were similar in the two surgical groups, as were the volumes of the lesions, although the profile of postoperative impairment in a spatial learning task differed between the lesion groups depending on the anesthetic regimen used. These results show that the choice of anesthetic protocol is a critical variable in designing behavioral neuroscience experiments using neurosurgical procedures. This factor should be considered carefully in experimental design and in cross-study comparisons of lesion effects on behavior. © 2007 Wiley-Liss, Inc.
doi:10.1002/hipo.20390
PMCID: PMC2386959  PMID: 18058823
hippocampus; spatial memory; learning; surgery; refinement
14.  Different behavioral effects of neurotoxic dorsal hippocampal lesions placed under either isoflurane or propofol anesthesia 
Hippocampus  2008;18(3):245-250.
Anesthetic protocols for behavioral neuroscience experiments are evolving as new anesthetics are developed and surgical procedures are refined to improve animal welfare. We tested whether neurotoxic dorsal hippocampal lesions produced under two different anesthetic protocols would have different behavioral and/or histopathological effects. Rats were anesthetized with either propofol, an intravenous anesthetic, or isoflurane, a gaseous anesthetic, and multiple injections of an excitotoxin (N-methyl-D-aspartate) were stereotaxically placed in the dorsal hippocampus bilaterally. Intraoperative physiological parameters were similar in the two surgical groups, as were the volumes of the lesions, although the profile of postoperative impairment in a spatial learning task differed between the lesion groups depending on the anesthetic regimen used. These results show that the choice of anesthetic protocol is a critical variable in designing behavioral neuroscience experiments using neurosurgical procedures. This factor should be considered carefully in experimental design and in cross-study comparisons of lesion effects on behavior.
doi:10.1002/hipo.20390
PMCID: PMC2386959  PMID: 18058823
hippocampus; spatial memory; learning; surgery; refinement
15.  Orbital prefrontal cortex is required for object-in-place scene memory but not performance of a strategy implementation task 
The orbital prefrontal cortex is thought to be involved in behavioral flexibility in primates, and human neuroimaging studies have identified orbital prefrontal activation during episodic memory encoding. The goal of the present study was to ascertain whether deficits in strategy implementation and episodic memory that occur after ablation of the entire prefrontal cortex can be ascribed to damage to the orbital prefrontal cortex. Rhesus monkeys were preoperatively trained on two behavioral tasks, performance of both of which is severely impaired by the disconnection of frontal cortex from inferotemporal cortex. In the strategy implementation task, monkeys were required to learn about two categories of objects, each associated with a different strategy that had to be performed to obtain food reward. The different strategies had to be applied flexibly in order to optimize the rate of reward delivery. In the scene memory task, monkeys learned 20 new object-in-place discrimination problems in each session. Monkeys were tested on both tasks before and after bilateral ablation of orbital prefrontal cortex. These lesions impaired new scene learning but had no effect on strategy implementation. This finding supports a role for the orbital prefrontal cortex in memory, but places limits on the involvement of orbital prefrontal cortex in the representation and implementation of behavioral goals and strategies.
doi:10.1523/JNEUROSCI.3369-07.2007
PMCID: PMC2092501  PMID: 17942727
macaque; frontal; rule; learning; category; episodic
16.  Neurotoxic lesions of ventrolateral prefrontal cortex impair object-in-place scene memory 
The European journal of neuroscience  2007;25(8):2514-2522.
Disconnection of the frontal lobe from the inferotemporal cortex produces deficits in a number of cognitive tasks that require the application of memory-dependent rules to visual stimuli. The specific regions of frontal cortex that interact with the temporal lobe in performance of these tasks remain undefined. One capacity that is impaired by frontal-temporal disconnection is rapid learning of new object-in-place scene problems, in which visual discriminations between two small typographic characters are learned in the context of different visually complex scenes. In the present study, we examined whether neurotoxic lesions of ventrolateral prefrontal cortex in one hemisphere, combined with ablation of inferior temporal cortex in the contralateral hemisphere, would impair learning of new object-in-place scene problems. Male macaque monkeys learned 10 or 20 new object-in-place problems in each daily test session. Unilateral neurotoxic lesions of ventrolateral prefrontal cortex produced by multiple injections of a mixture of ibotenate and N-methyl-D-aspartate did not affect performance. However, when disconnection from inferotemporal cortex was completed by ablating this region contralateral to the neurotoxic prefrontal lesion, new learning was substantially impaired. Sham disconnection (injecting saline instead of neurotoxin contralateral to the inferotemporal lesion) did not affect performance. These findings support two conclusions: first, that the ventrolateral prefrontal cortex is a critical area within the frontal lobe for scene memory; and second, the effects of ablations of prefrontal cortex can be confidently attributed to the loss of cell bodies within the prefrontal cortex, rather than to interruption of fibers of passage through the lesioned area.
doi:10.1111/j.1460-9568.2007.05468.x
PMCID: PMC1855623  PMID: 17445247
Macaque; Monkey; Episodic; Memory; Prefrontal
17.  Asymmetry of attentional set in rhesus monkeys learning colour and shape discriminations 
We trained rhesus monkeys on six visual discrimination problems using stimuli that varied in both shape and colour. For one group of animals shape was always relevant in these six problems, and colour always irrelevant, and for the other animals vice versa. During these “intradimensional shifts” (ID) the problems were learned at equal rates by the two groups, shape-relevant and colour-relevant. We then trained three further problems in which the other dimension was now relevant (“extradimensional shifts”, ED). The animals showed slower learning when shifting from colour-relevant to shape-relevant, but not when shifting from shape-relevant to colour-relevant. These results show that monkeys' ability to selectively attend to a relevant stimulus dimension and to ignore an irrelevant dimension depends on the experimenter's choice of relevant and irrelevant dimensions.
doi:10.1080/17470210600971485
PMCID: PMC1764629  PMID: 17162503
18.  Asymmetry of Attentional Set in Rhesus Monkeys Learning Color and Shape Discriminations 
We trained Rhesus monkeys on six visual discrimination problems using stimuli which varied in both shape and color. For one group of animals shape was always relevant in these six problems and color always irrelevant, and for the other animals vice versa. During these “intradimensional shifts” (ID) the problems were learned at equal rates by the two groups, shape-relevant and color-relevant. We then trained three further problems in which the other dimension was now relevant (“extradimensional shifts”, ED). The animals showed slower learning when shifting from color-relevant to shape-relevant, but not when shifting from shape-relevant to color-relevant. These results show that monkeys’ ability to selectively attend to a relevant stimulus dimension and to ignore an irrelevant dimension depends on the experimenter’s choice of relevant and irrelevant dimensions.
doi:10.1080/17470210600971485
PMCID: PMC1764629  PMID: 17162503
19.  Neurotoxic lesions of ventrolateral prefrontal cortex impair object-in-place scene memory 
The European Journal of Neuroscience  2007;25(8):2514-2522.
Disconnection of the frontal lobe from the inferotemporal cortex produces deficits in a number of cognitive tasks that require the application of memory-dependent rules to visual stimuli. The specific regions of frontal cortex that interact with the temporal lobe in performance of these tasks remain undefined. One capacity that is impaired by frontal–temporal disconnection is rapid learning of new object-in-place scene problems, in which visual discriminations between two small typographic characters are learned in the context of different visually complex scenes. In the present study, we examined whether neurotoxic lesions of ventrolateral prefrontal cortex in one hemisphere, combined with ablation of inferior temporal cortex in the contralateral hemisphere, would impair learning of new object-in-place scene problems. Male macaque monkeys learned 10 or 20 new object-in-place problems in each daily test session. Unilateral neurotoxic lesions of ventrolateral prefrontal cortex produced by multiple injections of a mixture of ibotenate and N-methyl-d-aspartate did not affect performance. However, when disconnection from inferotemporal cortex was completed by ablating this region contralateral to the neurotoxic prefrontal lesion, new learning was substantially impaired. Sham disconnection (injecting saline instead of neurotoxin contralateral to the inferotemporal lesion) did not affect performance. These findings support two conclusions: first, that the ventrolateral prefrontal cortex is a critical area within the frontal lobe for scene memory; and second, the effects of ablations of prefrontal cortex can be confidently attributed to the loss of cell bodies within the prefrontal cortex rather than to interruption of fibres of passage through the lesioned area.
doi:10.1111/j.1460-9568.2007.05468.x
PMCID: PMC1855623  PMID: 17445247
episodic; macaque; memory; monkey; prefrontal
20.  RATS EXPOSED TO ISOFLURANE IN UTERO DURING EARLY GESTATION ARE BEHAVIORALLY ABNORMAL AS ADULTS 
Anesthesiology  2011;114(3):521-528.
Background
Preclinical evidence suggests that commonly used anesthetic agents induce long-lasting neurobehavioral changes when administered early in life but there has been virtually no attention to the neurodevelopmental consequences for the fetus of maternal anesthesia. This study tested the hypothesis that fetal rats exposed to isoflurane during maternal anesthesia on gestational day 14, which corresponds to the second trimester in humans, would be behaviorally abnormal as adults.
Methods
Timed, pregnant rats were randomly assigned on gestational day 14 to receive 1.4% isoflurane in 100% oxygen (N = 3) or 100 % oxygen (N = 2) for 4 h. Beginning at 8 weeks of age, male offspring were evaluated for spontaneous locomotor activity, hippocampal dependent learning and memory (spontaneous alternations, novel object recognition, and radial arm maze), and anxiety (elevated plus maze).
Results
Isoflurane anesthesia was physiologically well tolerated by the dams. Adult rats exposed prenatally to isoflurane were not different than controls on spontaneous locomotor activity, spontaneous alternations, or object recognition memory but made more open arm entries on the elevated plus maze and took longer and made more errors of omission on the radial arm maze.
Conclusions
Rats exposed to isoflurane in utero at a time that corresponds to the second trimester in humans have impaired spatial memory acquisition and, reduced anxiety compared to controls. This suggests the fetal brain may be adversely affected by maternal anesthesia and raises the possibility that vulnerability to deleterious neurodevelopmental effects of isoflurane begins much earlier in life than previously recognized.
doi:10.1097/ALN.0b013e318209aa71
PMCID: PMC3071297  PMID: 21307768
21.  DIFFUSION-WEIGHTED IMAGING TRACTOGRAPHY-BASED PARCELLATION OF THE HUMAN PARIETAL CORTEX AND COMPARISON WITH HUMAN AND MACAQUE RESTING STATE FUNCTIONAL CONNECTIVITY 
Despite the prominence of parietal activity in human neuromaging investigations of sensorimotor and cognitive processes there remains uncertainty about basic aspects of parietal cortical anatomical organization. Descriptions of human parietal cortex draw heavily on anatomical schemes developed in other primate species but the validity of such comparisons has been questioned by claims that there are fundamental differences between the parietal cortex in humans and other primates. A scheme is presented for parcellation of human lateral parietal cortex into component regions on the basis of anatomical connectivity and the functional interactions of the resulting clusters with other brain regions. Anatomical connectivity was estimated using diffusion-weighted magnetic resonance image (MRI) based tractography and functional interactions were assessed by correlations in activity measured with functional MRI (fMRI) at rest. Resting state functional connectivity was also assessed directly in the rhesus macaque lateral parietal cortex in an additional experiment and the patterns found reflected known neuroanatomical connections. Cross-correlation in the tractography-based connectivity patterns of parietal voxels reliably parcellated human lateral parietal cortex into ten component clusters. The resting state functional connectivity of human superior parietal and intraparietal clusters with frontal and extrastriate cortex suggested correspondences with areas in macaque superior and intraparietal sulcus. Functional connectivity patterns with parahippocampal cortex and premotor cortex again suggested fundamental correspondences between inferior parietal cortex in humans and macaques. In contrast, the human parietal cortex differs in the strength of its interactions between the central inferior parietal lobule region and the anterior prefrontal cortex.
doi:10.1523/JNEUROSCI.5102-10.2011
PMCID: PMC3091022  PMID: 21411650
AIP; MIP; LIP; VIP; IPL; SPL
22.  Functional localization within the prefrontal cortex: missing the forest for the trees? 
Trends in Neurosciences  2010;33(12):533-540.
Anatomical and functional studies of the prefrontal cortex (PFC) have identified multiple PFC subregions. We argue that the PFC is involved in cognitive functions exceeding the sum of specific functions attributed to its subregions. These can be revealed either by lesions of the whole PFC, or more specifically by selective disconnection of the PFC from certain types of information (for example, visual) allowing the investigation of PFC function in toto. Recent studies in macaque monkeys using the latter approach lead to a second conclusion: that the PFC, as a whole, could be fundamentally specialized for representing events that are extended in time. The representation of temporally complex events might underlie PFC involvement in general intelligence, decision-making, and executive function.
doi:10.1016/j.tins.2010.08.001
PMCID: PMC2997428  PMID: 20864190
23.  The rostromedial tegmental nucleus (RMTg), a major GABAergic afferent to midbrain dopamine neurons, selectively encodes aversive stimuli and promotes behavioral inhibition 
Neuron  2009;61(5):786-800.
Summary
Separate studies have implicated the lateral habenula (LHb) or amygdala-related regions in processing aversive stimuli, but their relationships to each other and to appetitive motivational systems are poorly understood. We show that neurons in the recently identified GABAergic rostromedial tegmental nucleus (RMTg), which receive a major LHb input, project heavily to midbrain dopamine neurons, and show phasic activations and/or Fos induction after aversive stimuli (footshocks, shock-predictive cues, food deprivation, or reward omission) and inhibitions after rewards or reward-predictive stimuli. RMTg lesions markedly reduce passive fear behaviors (freezing, open-arm avoidance) dependent on the extended amygdala, periaqueductal gray, or septum, all regions that project directly to the RMTg. In contrast, RMTg lesions spare or enhance active fear responses (treading, escape) in these same paradigms. These findings suggest that aversive inputs from widespread brain regions and stimulus modalities converge onto the RMTg, which opposes reward and motor-activating functions of midbrain dopamine neurons
doi:10.1016/j.neuron.2009.02.001
PMCID: PMC2841475  PMID: 19285474
24.  Severe Scene Learning Impairment, but Intact Recognition Memory, after Cholinergic Depletion of Inferotemporal Cortex Followed by Fornix Transection 
Cerebral Cortex (New York, NY)  2009;20(2):282-293.
To examine the generality of cholinergic involvement in visual memory in primates, we trained macaque monkeys either on an object-in-place scene learning task or in delayed nonmatching-to-sample (DNMS). Each monkey received either selective cholinergic depletion of inferotemporal cortex (including the entorhinal cortex and perirhinal cortex) with injections of the immunotoxin ME20.4-saporin or saline injections as a control and was postoperatively retested. Cholinergic depletion of inferotemporal cortex was without effect on either task. Each monkey then received fornix transection because previous studies have shown that multiple disconnections of temporal cortex can produce synergistic impairments in memory. Fornix transection mildly impaired scene learning in monkeys that had received saline injections but severely impaired scene learning in monkeys that had received cholinergic lesions of inferotemporal cortex. This synergistic effect was not seen in monkeys performing DNMS. These findings confirm a synergistic interaction in a macaque monkey model of episodic memory between connections carried by the fornix and cholinergic input to the inferotemporal cortex. They support the notion that the mnemonic functions tapped by scene learning and DNMS have dissociable neural substrates. Finally, cholinergic depletion of inferotemporal cortex, in this study, appears insufficient to impair memory functions dependent on an intact inferotemporal cortex.
doi:10.1093/cercor/bhp097
PMCID: PMC2803729  PMID: 19447862
acetylcholine; hippocampus; macaque; monkey; temporal lobe
25.  Dorsolateral prefrontal lesions do not impair tests of scene learning and decision-making that require frontal–temporal interaction 
Theories of dorsolateral prefrontal cortex (DLPFC) involvement in cognitive function variously emphasize its involvement in rule implementation, cognitive control, or working and/or spatial memory. These theories predict broad effects of DLPFC lesions on tests of visual learning and memory. We evaluated the effects of DLPFC lesions (including both banks of the principal sulcus) in rhesus monkeys on tests of scene learning and strategy implementation that are severely impaired following crossed unilateral lesions of frontal cortex and inferotemporal cortex. Dorsolateral lesions had no effect on learning of new scene problems postoperatively, or on the implementation of preoperatively acquired strategies. They were also without effect on the ability to adjust choice behaviour in response to a change in reinforcer value, a capacity that requires interaction between the amygdala and frontal lobe. These intact abilities following DLPFC damage support specialization of function within the prefrontal cortex, and suggest that many aspects of memory and strategic and goal-directed behaviour can survive ablation of this structure.
doi:10.1111/j.1460-9568.2008.06353.x
PMCID: PMC2522287  PMID: 18702721
episodic; frontal cortex; macaque; memory; strategy

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