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1.  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.
PMCID: PMC3797511  PMID: 23739963
prefrontal; recognition memory; temporal cortex; novelty; object learning
2.  Neuronal and morphological bases of cognitive decline in aged rhesus monkeys 
Age  2011;34(5):1051-1073.
Rhesus monkeys provide a valuable model for studying the basis of cognitive aging because they are vulnerable to age-related decline in executive function and memory in a manner similar to humans. Some of the behavioral tasks sensitive to the effects of aging are the delayed response working memory test, recognition memory tests including the delayed nonmatching-to-sample and the delayed recognition span task, and tests of executive function including reversal learning and conceptual set-shifting task. Much effort has been directed toward discovering the neurobiological parameters that are coupled to individual differences in age-related cognitive decline. Area 46 of the dorsolateral prefrontal cortex (dlPFC) has been extensively studied for its critical role in executive function while the hippocampus and related cortical regions have been a major target of research for memory function. Some of the key age-related changes in area 46 include decreases in volume, microcolumn strength, synapse density, and α1- and α2-adrenergic receptor binding densities. All of these measures significantly correlate with cognitive scores. Interestingly, the critical synaptic subtypes associated with cognitive function appear to be different between the dlPFC and the hippocampus. For example, the dendritic spine subtype most critical to task acquisition and vulnerable to aging in area 46 is the thin spine, whereas in the dentate gyrus, the density of large mushroom spines with perforated synapses correlates with memory performance. This review summarizes age-related changes in anatomical, neuronal, and synaptic parameters within brain areas implicated in cognition and whether these changes are associated with cognitive decline.
PMCID: PMC3448991  PMID: 21710198
Aging; Area 46; Dentate gyrus; Executive function; Recognition memory; Perforated synapse
3.  Synaptic characteristics of dentate gyrus axonal boutons and their relationships with aging, menopause, and memory in female rhesus monkeys 
Age-related memory impairment occurs in many mammalian species including humans. Moreover, women undergoing the menopausal transition often complain of problems with memory. We recently reported that rhesus monkeys display age- and menopause-related recognition memory impairment on a hippocampus-reliant test (delayed nonmatching-to-sample; DNMS). In the same monkeys, perforated synapse densities in the dentate gyrus outer molecular layer (OML) correlated with DNMS recognition accuracy, while total axospinous synapse density was similar across age and menses groups. The current study examined whether synaptic characteristics of OML axonal boutons are coupled with age- or menopause-related memory deficits. Using serial section electron microscopy, we measured the frequencies of single-synapse boutons (SSBs), multiple-synapse boutons (MSBs), and boutons with no apparent synaptic contacts (non-synaptic boutons, NSBs) in the OML. Aged females had double the percentage of NSBs as compared to young females and this measure correlated positively and inversely with DNMS acquisition (number of trials to criterion) and delay performance (average accuracy), respectively. Aged compared to young females also had a lower frequency of MSBs and a lower number of synaptic contacts per MSB, and the latter variable inversely correlated with DNMS acquisition. Although proportions of NSBs, SSBs and MSBs were similar across menses groups, compared to pre-menopausal monkeys, peri/post-menopausal monkeys had fewer MSBs contacting one or more segmented perforated synapse and the abundance of this bouton subtype positively correlated with DNMS performance. These results suggest that age- and menopause-related shifts in OML synaptic subtypes may be coupled with deficits in task acquisition and recognition memory.
PMCID: PMC3103072  PMID: 21613486
delayed nonmatching-to-sample test; menopause; multiple-synapse bouton; serial sections; recognition memory
4.  Selective changes in thin spine density and morphology in monkey prefrontal cortex correlate with aging-related cognitive impairment 
Age-associated memory impairment (AAMI) occurs in many mammalian species including humans. In contrast to Alzheimer’s disease (AD) where circuit disruption occurs through neuron death, AAMI is due to circuit and synapse disruption in the absence of significant neuron loss and thus may be more amenable to prevention or treatment. We have investigated the effects of aging on pyramidal neurons and synapse density in Layer III of area 46 in dorsolateral prefrontal cortex of young and aged, male and female Rhesus monkeys (Macaca mulatta) that were tested for cognitive status through the delayed non-matching-to-sample (DNMS) and delayed response (DR) tasks. Cognitive tests revealed an age-related decrement in both acquisition and performance on DNMS. Our morphometric analyses revealed both an age-related loss of spines (33%, p< 0.05) on pyramidal cells and decreased density of axo-spinous synapses (32%, p<0.01) in layer III of area 46. In addition, there was an age-related shift in the distribution of spine types reflecting a selective vulnerability of small, thin spines, thought to be particularly plastic and linked to learning. While both synapse density and the overall spine size average of an animal were predictive of number of trials required for acquisition of DNMS (i.e., learning the task), the strongest correlate of behavior was found to be the head volume of thin spines, with no correlation between behavior and mushroom spine size or density. No synaptic index correlated with memory performance once the task was learned.
PMCID: PMC2892969  PMID: 20519525
aging; dendritic spines; primate; prefrontal cortex; cognition; plasticity
5.  Synaptic distributions of GluA2 and PKM ζ in the monkey dentate gyrus and their relationships with aging and memory 
The Journal of Neuroscience  2012;32(21):7336-7344.
Rhesus monkeys provide a valuable model for studying the neurobiological basis of cognitive aging, because they are vulnerable to age-related memory decline in a manner similar to humans. In this study, young and aged monkeys were first tested on a well-characterized recognition memory test (delayed nonmatching-to-sample; DNMS). Then, electron microscopic immunocytochemistry was performed to determine the subcellular localization of two proteins in the hippocampal dentate gyrus (DG): the GluA2 subunit of the glutamate alpha-amino-3-hydroxyl-5-methyl-4-isoxazole propionate (AMPA) receptor and the atypical protein kinase C ζ isoform (PKMζ). PKMζ promotes memory storage by regulating GluA2-containing AMPA receptor trafficking. Thus, we examined whether the distribution of GluA2 and PKMζ is altered with aging in DG axospinous synapses and whether it is coupled with memory deficits. Monkeys with faster DNMS task acquisition and more accurate recognition memory exhibited higher proportions of dendritic spines coexpressing GluA2 and PKMζ. These double-labeled spines had larger synapses, as measured by postsynaptic density area, than single- and unlabeled spines. Within this population of double-labeled spines, aged monkeys compared to young expressed a lower density of synaptic GluA2 immunogold labeling, which correlated with lower recognition accuracy. Additionally, higher density of synaptic PKMζ labeling in double-labeled spines correlated with both faster task acquisition and better retention. Together, these findings suggest that age-related impairment in maintenance of GluA2 at the synapse in the primate hippocampus is coupled with memory deficits.
PMCID: PMC3391702  PMID: 22623679
AMPA receptor; delayed nonmatching-to-sample test; GluR2; immunogold; PKMζ; recognition memory
6.  Impairment in Delayed Non-Matching to Sample Following Lesions of Dorsal Prefrontal Cortex 
Behavioral neuroscience  2012;126(6):772-780.
The prefrontal cortex has been identified as essential for executive function, as well as for aspects of rule learning and recognition memory. As part of our studies to assess prefrontal cortical function in the monkey, we evaluated the effects of damage to the dorsal prefrontal cortex (DPFC) on the Category Set Shifting Task (CSST), a test of abstraction and set-shifting, and on the Delayed Non Matching-to-Sample (DNMS) task, a benchmark test of rule learning and recognition memory. The DPFC lesions in this study included dorsolateral and dorsomedial aspects of the PFC. In a previous report, we published evidence of an impairment on the CSST as a consequence of DPFC lesions (Moore et al, 2009). Here we report that monkeys with lesions of the DPFC were also markedly impaired relative to controls on both the acquisition (rule learning) and performance (recognition memory) conditions of trial-unique DNMS. The presence and extent of the deficits that we observed were of some surprise and support the possibility that the dorsal prefrontal cortex plays a more direct role in learning and recognition memory than had been previously thought.
PMCID: PMC3518867  PMID: 23088539
Dorsal prefrontal cortex; Delayed Non-matching to Sample; Recognition memory; Rule learning; Rhesus monkey
7.  Short-Term Memory Trace in Rapidly Adapting Synapses of Inferior Temporal Cortex 
PLoS Computational Biology  2008;4(5):e1000073.
Visual short-term memory tasks depend upon both the inferior temporal cortex (ITC) and the prefrontal cortex (PFC). Activity in some neurons persists after the first (sample) stimulus is shown. This delay-period activity has been proposed as an important mechanism for working memory. In ITC neurons, intervening (nonmatching) stimuli wipe out the delay-period activity; hence, the role of ITC in memory must depend upon a different mechanism. Here, we look for a possible mechanism by contrasting memory effects in two architectonically different parts of ITC: area TE and the perirhinal cortex. We found that a large proportion (80%) of stimulus-selective neurons in area TE of macaque ITCs exhibit a memory effect during the stimulus interval. During a sequential delayed matching-to-sample task (DMS), the noise in the neuronal response to the test image was correlated with the noise in the neuronal response to the sample image. Neurons in perirhinal cortex did not show this correlation. These results led us to hypothesize that area TE contributes to short-term memory by acting as a matched filter. When the sample image appears, each TE neuron captures a static copy of its inputs by rapidly adjusting its synaptic weights to match the strength of their individual inputs. Input signals from subsequent images are multiplied by those synaptic weights, thereby computing a measure of the correlation between the past and present inputs. The total activity in area TE is sufficient to quantify the similarity between the two images. This matched filter theory provides an explanation of what is remembered, where the trace is stored, and how comparison is done across time, all without requiring delay period activity. Simulations of a matched filter model match the experimental results, suggesting that area TE neurons store a synaptic memory trace during short-term visual memory.
Author Summary
To know whether one is looking at an object seen a few seconds ago or not depends on visual short-term memory. To study short-term memory, we recorded single neuronal activity from two brain areas of monkeys, the TE and the perirhinal cortex of the temporal lobe, known to be important in visual pattern recognition and memory. The monkeys performed a short-term visual memory task, a sequential match-to-sample. The monkeys had to signal when a sample stimulus reappeared in a short sequence of stimuli. In area TE only, small fluctuations occurring for a sample-elicited response were correlated with the responses when a match stimulus reappeared, as if a snapshot of the sample-induced response was stored and recalled. In our modeling, we propose that each TE neuron stores and compares the signals during short-term memory by storing the response to the sample in local and rapidly adapting synapses. Subsequent stimulus-elicited responses are then automatically multiplied by the locally stored signal. Here, we show that the match can be detected when the sum of the outputs of the population of TE neurons crosses a threshold. Correlated fluctuations will be a signature this type of local memory storage wherever it occurs in the brain.
PMCID: PMC2366068  PMID: 18464917
8.  Working Memory Performance Correlates with Prefrontal-Hippocampal Theta Interactions but not with Prefrontal Neuron Firing Rates 
Performance of memory tasks is impaired by lesions to either the medial prefrontal cortex (mPFC) or the hippocampus (HPC); although how these two areas contribute to successful performance is not well understood. mPFC unit activity is temporally affected by hippocampal-theta oscillations, with almost half the mPFC population entrained to theta in behaving animals, pointing to theta interactions as the mechanism enabling collaborations between these two areas. mPFC neurons respond to sensory stimuli and responses in working memory tasks, though the function of these correlated firing rate changes remains unclear because similar responses are reported during mPFC dependent and independent tasks. Using a DNMS task we compared error trials vs. correct trials and found almost all mPFC cells fired at similar rates during both error and correct trials (92%), however theta-entrainment of mPFC neurons declined during error performance as only 17% of cells were theta-entrained (during correct trials 46% of the population was theta-entrained). Across the population, error and correct trials did not differ in firing rate, but theta-entrainment was impaired. Periods of theta-entrainment and firing rate changes appeared to be independent variables, and only theta-entrainment was correlated with successful performance, indicating mPFC-HPC theta-range interactions are the key to successful DNMS performance.
PMCID: PMC2861479  PMID: 20431726
working memory; prefrontal cortex; hippocampus; theta rhythm
9.  Working memory for temporal order is impaired after selective neonatal hippocampal lesions in adult rhesus macaques 
Behavioural brain research  2012;239:55-62.
A previous study in this laboratory demonstrated, for the first time, that neonatal lesions of the hippocampus impair monitoring working memory, as measured by a self-order task, but spare recency memory, as measured by the session-unique delayed nonmatching task. To substantiate and extend this novel finding, we assessed working memory in these same animals using a serial order memory task. In humans and non-human primates the serial order memory task has been shown to be dependent upon the integrity of the dorsolateral prefrontal cortex. Additionally, the serial order task has the ability to examine the integrity of non-dorsolateral dependent working memory functions, providing specificity to conclusions drawn from this task. Thus, monkeys with neonatal lesions of the hippocampus and sham-operated control subjects were tested on two versions of the serial order memory task (3 and 4 object). The results of this study demonstrated that neonatal hippocampal lesions did not impair performance on the 3-object version of the task, confirming our previous finding of intact non-dlPFC dependent working memory. In contrast, these same animals showed a significant impairment on the dlPFC dependent phase of the 4-object serial order task. This finding was further confirmed through a series of probe trials. These results, in combination with our earlier finding, suggest that early lesions of the hippocampus may have impacted the function of the dlPFC or its interactions with the hippocampus.
PMCID: PMC3804023  PMID: 23137699
dlPFC; schizophrenia; hippocampus; monkey
10.  White Matter Changes Compromise Prefrontal Cortex Function in Healthy Elderly Individuals 
Journal of cognitive neuroscience  2006;18(3):418-429.
Changes in memory function in elderly individuals are often attributed to dysfunction of the prefrontal cortex (PFC). One mechanism for this dysfunction may be disruption of white matter tracts that connect the PFC with its anatomical targets. Here, we tested the hypothesis that white matter degeneration is associated with reduced prefrontal activation. We used white matter hyperintensities (WMH), a magnetic resonance imaging (MRI) finding associated with cerebrovascular disease in elderly individuals, as a marker for white matter degeneration. Specifically, we used structural MRI to quantify the extent of WMH in a group of cognitively normal elderly individuals and tested whether these measures were predictive of the magnitude of prefrontal activity (fMRI) observed during performance of an episodic retrieval task and a verbal working memory task.
We also examined the effects of WMH located in the dorsolateral frontal regions with the hypothesis that dorsal PFC WMH would be strongly associated with not only PFC function, but also with areas that are anatomically and functionally linked to the PFC in a task-dependent manner. Results showed that increases in both global and regional dorsal PFC WMH volume were associated with decreases in PFC activity. In addition, dorsal PFC WMH volume was associated with decreased activity in medial temporal and anterior cingulate regions during episodic retrieval and decreased activity in the posterior parietal and anterior cingulate cortex during working memory performance. These results suggest that disruption of white matter tracts, especially within the PFC, may be a mechanism for age-related changes in memory functioning.
PMCID: PMC3776596  PMID: 16513006
11.  Stress-Induced Impairment of a Working Memory Task: Role of Spiking Rate and Spiking History Predicted Discharge 
PLoS Computational Biology  2012;8(9):e1002681.
Stress, pervasive in society, contributes to over half of all work place accidents a year and over time can contribute to a variety of psychiatric disorders including depression, schizophrenia, and post-traumatic stress disorder. Stress impairs higher cognitive processes, dependent on the prefrontal cortex (PFC) and that involve maintenance and integration of information over extended periods, including working memory and attention. Substantial evidence has demonstrated a relationship between patterns of PFC neuron spiking activity (action-potential discharge) and components of delayed-response tasks used to probe PFC-dependent cognitive function in rats and monkeys. During delay periods of these tasks, persistent spiking activity is posited to be essential for the maintenance of information for working memory and attention. However, the degree to which stress-induced impairment in PFC-dependent cognition involves changes in task-related spiking rates or the ability for PFC neurons to retain information over time remains unknown. In the current study, spiking activity was recorded from the medial PFC of rats performing a delayed-response task of working memory during acute noise stress (93 db). Spike history-predicted discharge (SHPD) for PFC neurons was quantified as a measure of the degree to which ongoing neuronal discharge can be predicted by past spiking activity and reflects the degree to which past information is retained by these neurons over time. We found that PFC neuron discharge is predicted by their past spiking patterns for nearly one second. Acute stress impaired SHPD, selectively during delay intervals of the task, and simultaneously impaired task performance. Despite the reduction in delay-related SHPD, stress increased delay-related spiking rates. These findings suggest that neural codes utilizing SHPD within PFC networks likely reflects an additional important neurophysiological mechanism for maintenance of past information over time. Stress-related impairment of this mechanism is posited to contribute to the cognition-impairing actions of stress.
Author Summary
When faced with stressful situations, normal thought processes can be impaired including the ability to focus attention or make decisions requiring deep thought. These effects can result in accidents at the workplace and in combat, jeopardizing the lives of others. To date, the effect of stress on the way neurons communicate and represent cognitive functions is poorly understood. Differing theories have provided opposing predictions regarding the effects of stress-related chemical changes in the brain on neuronal activity of the prefrontal cortex (PFC). In this study, we show that stress increases the discharge rate of PFC neurons during planning and assessment phases of a task requiring the PFC. Additionally, using a point process model of neuronal activity we show that stress, nonetheless, impairs the ability of PFC neurons to retain representations of past events over time. Together these findings suggest that stress-related impairment of cognitive function may involve deficits in the ability of PFC neurons to retain information about past events beyond changes in neuronal firing rates. We believe that this advancement provides new insight into the neural codes of higher cognitive function that may lead to the development of novel treatments for stress-related diseases and conditions involving PFC-dependent cognitive impairment.
PMCID: PMC3441423  PMID: 23028279
12.  What difference does a year of schooling make?: Maturation of brain response and connectivity between 2nd and 3rd grades during arithmetic problem solving 
NeuroImage  2011;57(3):796-808.
Early elementary schooling in 2nd and 3rd grades (ages 7-9) is an important period for the acquisition and mastery of basic mathematical skills. Yet, we know very little about neurodevelopmental changes that might occur over a year of schooling. Here we examine behavioral and neurodevelopmental changes underlying arithmetic problem solving in a well-matched group of 2nd (n = 45) and 3rd (n = 45) grade children. Although 2nd and 3rd graders did not differ on IQ or grade- and age-normed measures of math, reading and working memory, 3rd graders had higher raw math scores (effect sizes = 1.46-1.49) and were more accurate than 2nd graders in an fMRI task involving verification of simple and complex two-operand addition problems (effect size = 0.43). In both 2nd and 3rd graders, arithmetic complexity was associated with increased responses in right inferior frontal sulcus and anterior insula, regions implicated in domain-general cognitive control, and in left intraparietal sulcus (IPS) and superior parietal lobule (SPL) regions important for numerical and arithmetic processing. Compared to 2nd graders, 3rd graders showed greater activity in dorsal stream parietal areas right SPL, IPS and angular gyrus (AG) as well as ventral visual stream areas bilateral lingual gyrus (LG), right lateral occipital cortex (LOC) and right parahippocampal gyrus (PHG). Significant differences were also observed in the prefrontal cortex (PFC), with 3rd graders showing greater activation in left dorsal lateral PFC (dlPFC) and greater deactivation in the ventral medial PFC (vmPFC). Third graders also showed greater functional connectivity between the left dlPFC and multiple posterior brain areas, with larger differences in dorsal stream parietal areas SPL and AG, compared to ventral stream visual areas LG, LOC and PHG. No such between-grade differences were observed in functional connectivity between the vmPFC and posterior brain regions. These results suggest that even the narrow one-year interval spanning grades 2 and 3 is characterized by significant arithmetic task-related changes in brain response and connectivity, and argue that pooling data across wide age ranges and grades can miss important neurodevelopmental changes. Our findings have important implications for understanding brain mechanisms mediating early maturation of mathematical skills and, more generally, for educational neuroscience.
PMCID: PMC3165021  PMID: 21620984
arithmetic; children; intraparietal sulcus; dorsal lateral prefrontal cortex; fMRI
13.  Prefrontal contributions to domain-general executive control processes during temporal context retrieval 
Neuropsychologia  2007;46(4):1088-1103.
Neuroimaging studies have reported increased prefrontal cortex (PFC) activity during temporal context retrieval versus recognition memory. However, it remains unclear if these activations reflect PFC contributions to domain-general executive control processes or domain-specific retrieval processes. To gain a better understanding of the functional roles of these various PFC regions during temporal context retrieval we propose it is necessary to examine PFC activity across tasks from different domains, in which parallel manipulations are included targeting specific cognitive processes. In the current fMRI study, we examined domain-general and domain-specific PFC contributions to temporal context retrieval by increasing stimulus (but maintaining response number) and increasing response number (but maintaining stimulus number) across temporal context memory and ordering control tasks, for faces. The control task required subjects to order faces from youngest to oldest. Our behavioral results indicate that the combination of increased stimulus and response numbers significantly increased task difficulty for temporal context retrieval and ordering tasks. Across domains, increasing stimulus number, while maintaining response numbers, caused greater right lateral premotor cortex (BA 6/8) activity; whereas increasing response number, while maintaining stimulus number, caused greater domain-general left DLPFC (BA 9) and VLPFC (BA 44/45) activity. In addition, we found domain-specific right DLPFC (BA 9) activity only during retrieval events. These results highlight the functional heterogeneity of frontal cortex, and suggest its involvement in temporal context retrieval is related to its role in various cognitive control processes.
PMCID: PMC2703612  PMID: 18155254
episodic memory; working memory; selection; monitoring; face stimuli; fMRI
14.  Evaluating the role of prefrontal and parietal cortices in memory-guided response with repetitive transcranial magnetic stimulation 
Neuropsychologia  2008;47(2):295-302.
The dorsolateral prefrontal cortex (dlPFC) plays an important role in working memory, including the control of memory-guided response. In this study, with 24 subjects, we used high frequency repetitive transcranial magnetic stimulation (rTMS) to evaluate the role of the dlPFC in memory-guided response to two different types of spatial working memory tasks: one requiring a recognition decision about a probe stimulus (operationalized with a yes/no button press), another requiring direct recall of the memory stimulus by moving a cursor to the remembered location. In half the trials, randomly distributed, rTMS was applied to the dlPFC and in a separate session, the superior parietal lobule (SPL), a brain area implicated in spatial working memory storage. A 10-Hz (3 sec., 110% of motor threshold) train of TMS was delivered at the onset of the response period. We found that only dlPFC rTMS significantly affected performance, with rTMS of right dlPFC decreasing accuracy on delayed-recall trials, and rTMS of left and right dlPFC decreasing and enhancing accuracy, respectively, on delayed-recognition trials. These findings confirm that the dlPFC plays an important role in memory-guided response, and suggest that the nature of this role varies depending on the processes required for making a response.
PMCID: PMC2704005  PMID: 18822306
working memory; spatial; recall; recognition; response; TMS
15.  The association between aerobic fitness and executive function is mediated by prefrontal cortex volume 
Brain, Behavior, and Immunity  2011;26(5):811-819.
Aging is marked by a decline in cognitive function, which is often preceded by losses in gray matter volume. Fortunately, higher cardiorespiratory fitness (CRF) levels are associated with an attenuation of age-related losses in gray matter volume and a reduced risk for cognitive impairment. Despite these links, we have only a rudimentary understanding of whether fitness-related increases in gray matter volume lead to elevated cognitive function. In this cross-sectional study, we examined whether the association between higher aerobic fitness levels and elevated executive function was mediated by greater gray matter volume in the prefrontal cortex (PFC). One hundred and forty-two older adults (mean age = 66.6 years) completed structural magnetic resonance imaging (MRI) scans, CRF assessments, and performed Stroop and spatial working memory (SPWM) tasks. Gray matter volume was assessed using an optimized voxel-based morphometry approach. Consistent with our predictions, higher fitness levels were associated with (a) better performance on both the Stroop and SPWM tasks, and (b) greater gray matter volume in several regions, including the dorsolateral PFC (DLPFC). Volume of the right inferior frontal gyrus and precentral gyrus mediated the relationship between CRF and Stroop interference while a non-overlapping set of regions bilaterally in the DLPFC mediated the association between CRF and SPWM accuracy. These results suggest that specific regions of the DLPFC differentially relate to inhibition and spatial working memory. Thus, fitness may influence cognitive function by reducing brain atrophy in targeted areas in healthy older adults.
PMCID: PMC3321393  PMID: 22172477
cardiorespiratory fitness; executive function; voxel-based morphometry; cortical volume; prefrontal cortex; mediation
16.  Synaptic correlates of memory and menopause in the hippocampal dentate gyrus in rhesus monkeys 
Neurobiology of aging  2010;33(2):421.e17-421.e28.
Aged rhesus monkeys exhibit deficits in hippocampus-dependent memory, similar to aging humans. Here we explored the basis of cognitive decline by first testing young adult and aged monkeys on a standard recognition memory test (delayed nonmatching-to-sample test; DNMS). Next we quantified synaptic density and morphology in the hippocampal dentate gyrus (DG) outer (OML) and inner molecular layer (IML). Consistent with previous findings, aged monkeys were slow to learn DNMS initially, and they performed significantly worse than young subjects when challenged with longer retention intervals. Although OML and IML synaptic parameters failed to differ across the young and aged groups, the density of perforated synapses in the OML was coupled with recognition memory accuracy. Independent of chronological age, monkeys classified on the basis of menses data as peri/post-menopausal scored worse on DNMS, and displayed lower OML perforated synapse density, than pre-menopausal monkeys. These results suggest that naturally occurring reproductive senescence potently influences synaptic connectivity in the DG OML, contributing to individual differences in the course of normal cognitive aging.
PMCID: PMC3031995  PMID: 21030115
delayed nonmatching-to-sample; disector method; estrogen; hippocampus; menopause; outer molecular layer; perforated synapse; post-synaptic density; recognition memory
17.  Prefrontal Dynamics Underlying Rapid Instructed Task Learning Reverse with Practice 
The ability to rapidly reconfigure our minds to perform novel tasks is important for adapting to an ever-changing world, yet little is understood about its basis in the brain. Furthermore, it is unclear how this kind of task preparation changes with practice. Previous research suggests that prefrontal cortex (PFC) is essential when preparing to perform either novel or practiced tasks. Building upon recent evidence that PFC is organized in an anterior-to-posterior hierarchy, we postulated that novel and practiced task preparation would differentiate hierarchically distinct regions within PFC across time. Specifically, we hypothesized and confirmed using functional magnetic resonance imaging and magnetoencephalography with humans that novel task preparation is a bottom-up process that involves lower-level rule representations in dorsolateral PFC (DLPFC) before a higher-level rule-integrating task representation in anterior PFC (aPFC). In contrast, we identified a complete reversal of this activity pattern during practiced task preparation. Specifically, we found that practiced task preparation is a top-down process that involves a higher-level rule-integrating task representation (recalled from long-term memory) in aPFC before lower-level rule representations in DLPFC. These findings reveal two distinct yet highly inter-related mechanisms for task preparation, one involving task set formation from instructions during rapid instructed task learning and the other involving task set retrieval from long-term memory to facilitate familiar task performance. These two mechanisms demonstrate the exceptional flexibility of human PFC as it rapidly reconfigures cognitive brain networks to implement a wide variety of possible tasks.
PMCID: PMC3128837  PMID: 20962245
18.  Delay-period activity in prefrontal cortex: one function is sensory gating 
Journal of cognitive neuroscience  2005;17(11):1679-1690.
Prefrontal cortex (PFC) contributes to working memory functions via executive control processes that do not entail the storage, per se, of mnemonic representations. One of these control processes may be a sensory gating mechanism that facilitates retention of representations in working memory by down-regulating the gain of the sensory processing of intervening irrelevant stimuli. This idea was tested by scanning healthy young adults with functional magnetic resonance imaging while they performed a delayed face-recognition task. The 2 x 2 factorial design varied the factors of Memory (present, absent) and Distraction (present, absent). During memory-present trials, target and probe stimuli were individual gray-scale male faces. Memory-absent trials were identical, except that they employed the same recurring female faces (denoting a “no memory” trial). Distraction-present trials featured rapid serial visual presentation of bespectacled male faces during the two middle sec of the delay. The first step of the analyses identified dorsolateral PFC (dlPFC) and inferior occipitotemporal cortex (IOTC) voxels exhibiting delay-period activity in memory-present/distraction-absent trials – i.e., the “unfilled” delay. Within these voxels, distraction-evoked activity in dlPFC was markedly higher during trials that required the concurrent short-term retention of information than on those that did not, whereas the opposite effect was seen in IOTC. These results are consistent with the view that processes related to sensory gating account for a portion of the delay-period activity that is routinely observed in dorsolateral PFC.
PMCID: PMC1343532  PMID: 16269105
19.  Encoding of gustatory working memory by orbitofrontal neurons 
The content model regarding the functional organization of working memory in prefrontal cortex (PFC) states that different PFC areas encode different types of information in working memory depending upon their afferent connections with other brain areas. Previous studies that tested this model focused on visual, auditory and somatosensory information. However, posterior areas processing this information project to widespread and overlapping regions of lateral PFC, making it difficult to establish the veracity of the model. In contrast, gustatory information enters PFC via orbitofrontal cortex (OFC), and so the content model would argue that OFC should be responsible for maintaining gustatory information in working memory. To test this, we recorded the activity of single neurons throughout PFC and gustatory cortex (GUS) from two subjects while they performed a gustatory delayed-match-to-sample task with intervening gustatory distraction. Neurons that encoded the identity of the gustatory stimulus across the delay, consistent with a role in gustatory working memory, were most prevalent in OFC and GUS compared to DLPFC and VLPFC. Gustatory information in OFC was more resilient to intervening distraction, paralleling previous findings regarding visual working memory processes in PFC and posterior sensory cortex. Our findings provide support for the content model of working memory organization. Maintaining gustatory information may be one aspect of a wider function for OFC in reward working memory that could contribute to its role in decision-making.
PMCID: PMC2768394  PMID: 19158302
Prefrontal cortex; working memory; gustatory; executive; frontal; reward
Behavioural brain research  2010;208(2):584-592.
It is now well established that cannabinoid agonists such as D9–tetrahydrocannabinol (THC), anandamide, and WIN 55,212-2 (WIN-2) produce potent and specific deficits in working memory (WM)/short-term memory (STM) tasks in rodents. Although mediated through activation of CB1 receptors located in memory-related brain regions such as the hippocampus and prefrontal cortex, these may, in part, be due to a reduction in acetylcholine release (i.e., cholinergic hypofunction). To determine the interaction between cannabinoid and cholinergic systems, we exposed rats treated with WIN-2 or cholinergic drugs to a hippocampal-dependent delayed nonmatch to sample (DNMS) task to study STM, and recorded hippocampal single-unit activity in vivo. WIN-2 induced significant deficits in DNMS performance and reduced the average firing and bursting rates of hippocampal principal cells through a CB1 receptor-mediated mechanism. Rivastigmine, an acetylcholinesterase inhibitor, reversed these STM deficits and normalized hippocampal discharge rates. Effects were specific to 1 mg/kg WIN-2 as rivastigmine failed to reverse the behavioral and physiological deficits that were observed in the presence of MK-801, an NMDA receptor antagonist. This supports the notion that cannabinoid-modulated cholinergic activity is a mechanism underlying the performance deficits in DNMS. Whether deficits are due to reduced nicotinic or muscarinic receptor activation, or both, awaits further analysis.
PMCID: PMC3151156  PMID: 20079375
21.  Do inter-regional gray-matter volumetric correlations reflect altered functional connectivity in high-risk offspring of schizophrenia patients? 
Schizophrenia Research  2010;118(1-3):62-68.
Schizophrenia patients and their relatives show aberrant functional connectivity in default network regions (DRs) such as the medial prefrontal, lateral temporal, cingulate and inferior parietal cortices and executive regions such as the dorsolateral prefrontal cortex (DLPFC). Gray-matter volumetric alterations may be related to these functional connectivity deficits. Also, gray-matter volume inter-regional correlations may reflect altered inter-regional functional connectivity.
To examine our prediction of alterations of gray-matter volumes and inter-regional volume correlations for DRs and the DLPFC in offspring of schizophrenia patients (OS).
We assessed 64 adolescent and young adult OS and 80 healthy controls (HC) using T1-MRI. Regional gray-matter volumes and inter-regional volume correlations between the DRs and between the DLPFC and DRs on each side were compared across groups.
Compared to HC, OS had reductions in several DRs and the DLPFC after controlling age, gender, and intra-cranial volume, and correcting for multiple comparisons. OS had stronger (more positive) gray-matter volume inter-correlations between DRs and between DRs and the DLPFC.
Volumetric deficits in the default network and in the DLPFC may be related to familial diathesis to schizophrenia and to functional connectivity abnormalities in those at familial risk. Increased inter-correlations between DRs and between DR and DLPFC gray-matter volumes may serve as surrogate indices of abnormal functional connectivity.
PMCID: PMC3397169  PMID: 20171847
Default network; Dorso lateral prefrontal cortex; Inter-regional correlations; Functional connectivity
22.  Synaptic estrogen receptor-alpha levels in prefrontal cortex in female rhesus monkeys and their correlation with cognitive performance 
In rat hippocampus, estrogen receptor-alpha (ER-α) can initiate non-genomic signaling mechanisms that modulate synaptic plasticity in response to either circulating or locally synthesized estradiol (E). Here we report quantitative electron microscopic data demonstrating that ER-α is present within excitatory synapses in dorsolateral prefrontal cortex (dlPFC) of young and aged ovariectomized female rhesus monkeys with and without E treatment. There were no treatment or age effects on the percentage of excitatory synapses containing ER-α, nor were there any group differences in distribution of ER-α within the synapse. However, the mean size of synapses containing ER-α was larger than unlabeled excitatory synapses. All monkeys were tested on delayed response (DR), a cognitive test of working memory that requires dlPFC. In young ovariectomized monkeys without E treatment, presynaptic ER-α correlated with DR accuracy across memory delays. In aged monkeys that received E treatment, ER-α within the postsynaptic density (30–60 nm from the synaptic membrane) positively correlated with DR performance. Thus, while the lack of group effects suggests that ER-α is primarily in synapses that are stable across age and treatment, synaptic abundance of ER-α is correlated with individual performance in two key age/treatment groups. These data have important implications for individual differences in the cognitive outcome among menopausal women and promote a focus on cortical estrogen receptors for therapeutic efficacy with respect to cognition.
PMCID: PMC2951003  PMID: 20861381
estradiol; menopause; aging; cognition; dendritic spines; electron microscopy
23.  Recruitment of hippocampal neurons to encode behavioral events in the rat: Alterations in cognitive demand and cannabinoid exposure 
Hippocampus  2010;20(9):1083-1094.
Successful performance by rats of a delayed-nonmatch-to-sample (DNMS) task is hippocampal dependent. We have shown that neurons in hippocampus differentially encode task-relevant events. These responses are critical for correct DNMS performance and are diminished by exogenous cannabinoids. We therefore reasoned that hippocampal neural correlates of behavior are likely shaped during learning; however, to date, no work has examined these correlates during DNMS acquisition training. Consequently, the present study assessed the emergence of hippocampal neural encoding when (i) cognitive task demands were increased through prolongation of delay intervals between sample and nonmatch phase, and (ii) when animals are under cannabinoid treatment and performance is compromised. Adult, male Long-Evans rats were trained to perform the DNMS task without delay and then implanted with multi-electrode recording arrays directed to CA3 and CA1 sub-fields of the hippocampus. Following recovery, single units were isolated and animals divided into two treatment groups: vehicle or WIN 55,212-2 (WIN-2, 0.35 mg/kg). Ensemble firing was monitored during retraining in DNMS task at 0s, and subsequently delay intervals were progressively increased to 1–10s, 11–20s and 21–30s when animals met criterion (80% correct) at each respective interval. Hippocampal CA3 and CA1 principal cells were isolated and recorded throughout treatment. Extention of the delay led to an increase in the number of task-correlated neurons in controls. This recruitment of novel cells was reduced/prevented in the presence of WIN-2 and was paralleled by impairment in acquisition learning at longer delay intervals. Moreover, WIN-2 suppressed hippocampal ensemble firing during the sample (encoding) but not nonmatch phase of the DNMS task across all delays. These cannabinoid induced alterations in hippocampal neuronal activity may explain the observed deficits in DNMS performance.
PMCID: PMC2891278  PMID: 19771586
cannabinoids; hippocampus; ensemble; short-term memory; learning; delayed-non- match-to sample; electrophysiology
24.  Cognitive regulation during decision-making shifts behavioral control between ventromedial and dorsolateral prefrontal value systems 
Cognitive regulation is often used to influence behavioral outcomes. However, the computational and neurobiological mechanisms by which it affects behavior remain unknown. We studied this issue using an fMRI task in which human participants used cognitive regulation to up- and down-regulate their cravings for foods at the time of choice. We found that activity in both ventromedial prefrontal cortex (vmPFC) and dorsolateral prefrontal cortex (dlPFC) correlated with value. We also found evidence that two distinct regulatory mechanisms were at work: value modulation, which operates by changing the values assigned to foods in vmPFC and dlPFC at the time of choice, and behavioral control modulation, which operates by changing the relative influence of the vmPFC and dlPFC value signals on the action selection process used to make choices. In particular, during down-regulation, activation decreased in the value-sensitive region of dlPFC (indicating value modulation) but not in vmPFC, and the relative contribution of the two value signals to behavior shifted towards the dlPFC (indicating behavioral control modulation). The opposite pattern was observed during up-regulation: activation increased in vmPFC but not dlPFC, and the relative contribution to behavior shifted towards the vmPFC. Finally, ventrolateral PFC and posterior parietal cortex were more active during both up- and down-regulation, and were functionally connected with vmPFC and dlPFC during cognitive regulation, which suggests that they help to implement the changes to the decision-making circuitry generated by cognitive regulation.
PMCID: PMC3689006  PMID: 23015444
25.  Cognitive Regulation during Decision Making Shifts Behavioral Control between Ventromedial and Dorsolateral Prefrontal Value Systems 
The Journal of Neuroscience  2012;32(39):13543-13554.
Cognitive regulation is often used to influence behavioral outcomes. However, the computational and neurobiological mechanisms by which it affects behavior remain unknown. We studied this issue using an fMRI task in which human participants used cognitive regulation to upregulate and downregulate their cravings for foods at the time of choice. We found that activity in both ventromedial prefrontal cortex (vmPFC) and dorsolateral prefrontal cortex (dlPFC) correlated with value. We also found evidence that two distinct regulatory mechanisms were at work: value modulation, which operates by changing the values assigned to foods in vmPFC and dlPFC at the time of choice, and behavioral control modulation, which operates by changing the relative influence of the vmPFC and dlPFC value signals on the action selection process used to make choices. In particular, during downregulation, activation decreased in the value-sensitive region of dlPFC (indicating value modulation) but not in vmPFC, and the relative contribution of the two value signals to behavior shifted toward the dlPFC (indicating behavioral control modulation). The opposite pattern was observed during upregulation: activation increased in vmPFC but not dlPFC, and the relative contribution to behavior shifted toward the vmPFC. Finally, ventrolateral PFC and posterior parietal cortex were more active during both upregulation and downregulation, and were functionally connected with vmPFC and dlPFC during cognitive regulation, which suggests that they help to implement the changes to the decision-making circuitry generated by cognitive regulation.
PMCID: PMC3689006  PMID: 23015444

Results 1-25 (632307)