Theta Rhythms Coordinate Hippocampal–Prefrontal Interactions in a Spatial Memory Task

Decision-making requires the coordinated activity of diverse brain structures. For example, in maze-based tasks, the prefrontal cortex must integrate spatial information encoded in the hippocampus with mnemonic information concerning route and task rules in order to direct behavior appropriately. Using simultaneous tetrode recordings from CA1 of the rat hippocampus and medial prefrontal cortex, we show that correlated firing in the two structures is selectively enhanced during behavior that recruits spatial working memory, allowing the integration of hippocampal spatial information into a broader, decision-making network. The increased correlations are paralleled by enhanced coupling of the two structures in the 4- to 12-Hz theta-frequency range. Thus the coordination of theta rhythms may constitute a general mechanism through which the relative timing of disparate neural activities can be controlled, allowing specialized brain structures to both encode information independently and to interact selectively according to current behavioral demands.     

Developmental Sex Differences in Nicotinic Currents of Prefrontal Layer VI Neurons in Mice and Rats

Background

There is a large sex difference in the prevalence of attention deficit disorder; yet, relatively little is known about sex differences in the development of prefrontal attention circuitry. In male rats, nicotinic acetylcholine receptors excite corticothalamic neurons in layer VI, which are thought to play an important role in attention by gating the sensitivity of thalamic neurons to incoming stimuli. These nicotinic currents in male rats are significantly larger during the first postnatal month when prefrontal circuitry is maturing. The present study was undertaken to investigate whether there are sex differences in the nicotinic currents in prefrontal layer VI neurons during development.

Methodology/Principal Findings

Using whole cell recording in prefrontal brain slice, we examined the inward currents elicited by nicotinic stimulation in male and female rats and two strains of mice. We found a prominent sex difference in the currents during the first postnatal month when males had significantly greater nicotinic currents in layer VI neurons compared to females. These differences were apparent with three agonists: acetylcholine, carbachol, and nicotine. Furthermore, the developmental sex difference in nicotinic currents occurred despite male and female rodents displaying a similar pattern and proportion of layer VI neurons possessing a key nicotinic receptor subunit.

Conclusions/Significance

This is the first illustration at a cellular level that prefrontal attention circuitry is differently affected by nicotinic receptor stimulation in males and females during development. This transient sex difference may help to define the cellular and circuit mechanisms that underlie vulnerability to attention deficit disorder.     

Dynamic Spatial Organization of Receptive Fields of Neurons in the 21a Cortical Area

We studied changes in the spatial parameters of receptive fields (RFs) of visually sensitive neurons in the associative area 21a of the cat cortex under conditions of presentation of moving visual stimuli. The results of experiments demonstrated that these parameters are dynamic and depend, from many aspects, on the pattern of the stimulus used for their estimation. Angular lengths of the horizontal and vertical axes of the RFs measured in the case of movement of the visual stimuli exceeded many times those determined by presentation of stationary blinking stimuli. As is supposed, a visual stimulus, when moving along the field of vision, activates a certain number of the neurons synaptically connected with the examined cell and possessing RFs localized along the movement trajectory. As a result, such integrated activity of the neuronal group can change the excitation threshold and discharge frequency of the studied neuron. It seems probable that correlated directed activation of the neuronal groups represents a significant neurophysiological mechanism providing dynamic modifications of the RF parameters of visually sensitive neurons in the course of processes of visual perception and identification of moving objects within the field of vision.     

Variability of Prefrontal Neuronal Discharges before and after Training in a Working Memory Task

Variability of neural discharges can be revealing about the computations and network properties of neuronal populations during the performance of cognitive tasks. We sought to quantify neuronal variability in the prefrontal cortex of naïve monkeys that were only required to fixate, and to examine how this measure was altered by learning and execution of a working memory task. We therefore performed analysis of a large database of recordings in the same animals, using the same stimuli, before and after training. Our results indicate that the Fano Factor, a measure of variability, differs across neurons depending on their functional properties both before and after learning. Fano Factor generally decreased after learning the task. Variability was modulated by task events and displayed lowest values during the stimulus presentation. Nonetheless, the decrease in variability after training was present even prior to the presentation of any stimuli, in the fixation period. The greatest decreases were observed comparing populations of neurons that exhibited elevated firing rate during the trial events. Our results offer insights on how properties of the prefrontal network are affected by performance of a cognitive task.     

Activity in Inferior Parietal and Medial Prefrontal Cortex Signals the Accumulation of Evidence in a Probability Learning Task

In an uncertain environment, probabilities are key to predicting future events and making adaptive choices. However, little is known about how humans learn such probabilities and where and how they are encoded in the brain, especially when they concern more than two outcomes. During functional magnetic resonance imaging (fMRI), young adults learned the probabilities of uncertain stimuli through repetitive sampling. Stimuli represented payoffs and participants had to predict their occurrence to maximize their earnings. Choices indicated loss and risk aversion but unbiased estimation of probabilities. BOLD response in medial prefrontal cortex and angular gyri increased linearly with the probability of the currently observed stimulus, untainted by its value. Connectivity analyses during rest and task revealed that these regions belonged to the default mode network. The activation of past outcomes in memory is evoked as a possible mechanism to explain the engagement of the default mode network in probability learning. A BOLD response relating to value was detected only at decision time, mainly in striatum. It is concluded that activity in inferior parietal and medial prefrontal cortex reflects the amount of evidence accumulated in favor of competing and uncertain outcomes.     

The Tuning of Human Motor Response to Risk in a Dynamic Environment Task

The role of motor uncertainty in discrete or static space tasks, such as pointing tasks, has been investigated in many experiments. These studies have shown that humans hold an internal representation of intrinsic and extrinsic motor uncertainty and compensate for this variability when planning movement. The aim of this study was to investigate how humans respond to uncertainties during movement execution in a dynamic environment despite indeterminate knowledge of the outcome of actions. Additionally, the role of errors, or lack thereof, in predicting risk was examined. In the experiment, subjects completed a driving simulation game on a two-lane road. The road contained random curves so that subjects were forced to use sensory feedback to complete the task and could not rely only on motor planning. Risk was manipulated by using horizontal perturbations to create the illusion of driving on a bumpy road, thereby imposing motor uncertainty, and altering the cost function of the road. Results suggest continual responsiveness to cost and uncertainty in a dynamic task and provide evidence that subjects avoid risk even in the absence of errors. The results suggest that humans tune their statistical motor behavior based on cost, taking into account probabilities of possible outcomes in response to environmental uncertainty.     

Mortality Related to Acute Illness and Injury in Rural Uganda: Task Shifting to Improve Outcomes

Background

Due to the dual critical shortages of acute care and healthcare workers in resource-limited settings, many people suffer or die from conditions that could be easily treated if existing resources were used in a more timely and effective manner. In order to address this preventable morbidity and mortality, a novel emergency midlevel provider training program was developed in rural Uganda. This is the first study that assesses this unique application of a task-shifting model to acute care by evaluating the outcomes of 10,105 patients.

Methods

Nurses participated in a two-year training program to become midlevel providers called Emergency Care Practitioners at a rural district hospital. This is a retrospective analysis of the Emergency Department’s quality assurance database, including three-day follow-up data. Case fatality rates (CFRs) are reported as the percentage of cases with a specific diagnosis that died within three days of their Emergency Department visit.

Findings

Overall, three-day mortality was 2.0%. The most common diagnoses of patients who died were malaria (n=60), pneumonia (n=51), malnutrition (n=21), and trauma (n=18). Overall and under-five CFRs were as follows: malaria, 2.0% and 1.9%; pneumonia, 5.5% and 4.1%; and trauma, 1.2% and 1.6%. Malnutrition-related fatality (all cases <18 years old) was 6.5% overall and 6.8% for under-fives.

Interpretation

This study describes the outcomes of emergency patients treated by midlevel providers in a resource-limited setting. Our fatality rates are lower than previously published regional rates. These findings suggest this model of task-shifting can be successfully applied to acute care in order to address the shortage of emergency care services in similar settings as part of an integrated approach to health systems strengthening.     

Performing Permanent Distal Middle Cerebral with Common Carotid Artery Occlusion in Aged Rats to Study Cortical Ischemia with Sustained Disability

Stroke typically occurs in elderly people with a range of comorbidities including carotid (or other arterial) atherosclerosis, high blood pressure, obesity and diabetes. Accordingly, when evaluating therapies for stroke in animals, it is important to select a model with excellent face validity. Ischemic stroke accounts for 80% of all strokes, and the majority of these occur in the territory of the middle cerebral artery (MCA), often inducing infarcts that affect the sensorimotor cortex, causing persistent plegia or paresis on the contralateral side of the body. We demonstrate in this video a method for producing ischemic stroke in elderly rats, which causes sustained sensorimotor disability and substantial cortical infarcts. Specifically, we induce permanent distal middle cerebral artery occlusion (MCAO) in elderly female rats by using diathermy forceps to occlude a short segment of this artery. The carotid artery on the ipsilateral side to the lesion was then permanently occluded and the contralateral carotid artery was transiently occluded for 60 min. We measure the infarct size using structural T2-weighted magnetic resonance imaging (MRI) at 24 hr and 8 weeks after stroke. In this study, the mean infarct volume was 4.5% ± 2.0% (standard deviation) of the ipsilateral hemisphere at 24 hr (corrected for brain swelling using Gerriet’s equation, n = 5). This model is feasible and clinically relevant as it permits the induction of sustained sensorimotor deficits, which is important for the elucidation of pathophysiological mechanisms and novel treatments.     

Optogenetics in Mice Performing a Visual Discrimination Task: Measurement and Suppression of Retinal Activation and the Resulting Behavioral Artifact

Optogenetic techniques are used widely to perturb and interrogate neural circuits in behaving animals, but illumination can have additional effects, such as the activation of endogenous opsins in the retina. We found that illumination, delivered deep into the brain via an optical fiber, evoked a behavioral artifact in mice performing a visually guided discrimination task. Compared with blue (473 nm) and yellow (589 nm) illumination, red (640 nm) illumination evoked a greater behavioral artifact and more activity in the retina, the latter measured with electrical recordings. In the mouse, the sensitivity of retinal opsins declines steeply with wavelength across the visible spectrum, but propagation of light through brain tissue increases with wavelength. Our results suggest that poor retinal sensitivity to red light was overcome by relatively robust propagation of red light through brain tissue and stronger illumination of the retina by red than by blue or yellow light. Light adaptation of the retina, via an external source of illumination, suppressed retinal activation and the behavioral artifact without otherwise impacting behavioral performance. In summary, long wavelength optogenetic stimuli are particularly prone to evoke behavioral artifacts via activation of retinal opsins in the mouse, but light adaptation of the retina can provide a simple and effective mitigation of the artifact.     

Differential Interactions of Desipramine with Amphetamine and Methamphetamine: Evidence that Amphetamine Releases Dopamine from Noradrenergic Neurons in the Medial Prefrontal Cortex

Amphetamine is more effective than methamphetamine at raising dopamine levels in the prefrontal cortex. The current study tested the hypothesis that norepinephrine transporters are involved in this difference. Using microdialysis, dopamine, norepinephrine, and serotonin were measured in the rat prefrontal cortex after administration of methamphetamine or amphetamine, with and without perfusion of desipramine. Amphetamine raised norepinephrine levels more than methamphetamine did. Desipramine raised dopamine and serotonin levels but did not alter metabolite levels. Desipramine attenuated the increase in dopamine by amphetamine while increasing the dopamine released by methamphetamine. These data suggest that methamphetamine and amphetamine differ in altering prefrontal cortical dopamine levels and in interacting with norepinephrine transporters. It is proposed that amphetamine releases dopamine in the prefrontal cortex primarily through norepinephrine transporters, whereas methamphetamine interacts minimally with norepinephrine transporters.     

Dynamic Changes of CD44 Expression from Progenitors to Subpopulations of Astrocytes and Neurons in Developing Cerebellum

We previously reported that CD44-positive cells were candidates for astrocyte precursor cells in the developing cerebellum, because cells expressing high levels of CD44 selected by fluorescence-activated cell sorting (FACS) gave rise only to astrocytes in vitro. However, whether CD44 is a specific cell marker for cerebellar astrocyte precursor cells in vivo is unknown. In this study, we used immunohistochemistry, in situ hybridization, and FACS to analyze the spatial and temporal expression of CD44 and characterize the CD44-positive cells in the mouse cerebellum during development. CD44 expression was observed not only in astrocyte precursor cells but also in neural stem cells and oligodendrocyte precursor cells (OPCs) at early postnatal stages. CD44 expression in OPCs was shut off during oligodendrocyte differentiation. Interestingly, during development, CD44 expression was limited specifically to Bergmann glia and fibrous astrocytes among three types of astrocytes in cerebellum, and expression in astrocytes was shut off during postnatal development. CD44 expression was also detected in developing Purkinje and granule neurons but was limited to granule neurons in the adult cerebellum. Thus, at early developmental stages of the cerebellum, CD44 was widely expressed in several types of precursor cells, and over the course of development, the expression of CD44 became restricted to granule neurons in the adult.     

Differential Effects of Chloral Hydrate and Pentobarbital Sodium on a Cocaine Level and Its Catecholamine Response in the Medial Prefrontal Cortex: A Comparison with Conscious Rats

Abstract: Adult male Sprague-Dawley rats anesthetized with chloral hydrate and pentobarbital sodium were used as two different treatment groups. Conscious rats were used as a control group. By using baseline (precocaine) concentration as 100%, after cocaine administration (3.0 mg/kg i.v.), the maximal dopamine (DA) increase occurring at the first microdialysis collection period (20 min) in the medial prefrontal cortex was 299 ± 46% for the chloral hydrate group, 168 ± 12% for the pentobarbital sodium group, and 325 ± 23% for the conscious group. At the same time, norepinephrine (NA) increases reached a maximum and were 162 ± 20%, 100 ± 5%, and 141 ± 17%, respectively. The maximal changes of DA and NA in the chloral hydrate group and in the control group were both significantly higher than that in the pentobarbital sodium group. Meanwhile, the cocaine concentration was higher over a 100-min period of time in the chloral hydrate group when compared with the pentobarbital group and the control group. The peak cocaine concentration in dialysate occurred in the same time slot of maximal DA and NA responses, which were 0.65 ± 0.08, 0.30 ± 0.02, and 0.41 ± 0.05 µ M , respectively. Anesthetics suppress the pharmacologic response of neurons, which may explain the difference in catecholamine response between the pentobarbital sodium and the conscious groups. Conversely, because there was no significant difference in DA and NA response between the chloral hydrate group and the conscious group, it may possibly be due to the balancing effect between the higher existing cocaine concentration and the anesthetic suppression on pharmacological response of neurons in the chloral hydrate group. The effect of guide cannula implantation on the cocaine-induced catecholamine response was also evaluated.     

Spiking Neurons in a Hierarchical Self-Organizing Map Model Can Learn to Develop Spatial and Temporal Properties of Entorhinal Grid Cells and Hippocampal Place Cells

Medial entorhinal grid cells and hippocampal place cells provide neural correlates of spatial representation in the brain. A place cell typically fires whenever an animal is present in one or more spatial regions, or places, of an environment. A grid cell typically fires in multiple spatial regions that form a regular hexagonal grid structure extending throughout the environment. Different grid and place cells prefer spatially offset regions, with their firing fields increasing in size along the dorsoventral axes of the medial entorhinal cortex and hippocampus. The spacing between neighboring fields for a grid cell also increases along the dorsoventral axis. This article presents a neural model whose spiking neurons operate in a hierarchy of self-organizing maps, each obeying the same laws. This spiking GridPlaceMap model simulates how grid cells and place cells may develop. It responds to realistic rat navigational trajectories by learning grid cells with hexagonal grid firing fields of multiple spatial scales and place cells with one or more firing fields that match neurophysiological data about these cells and their development in juvenile rats. The place cells represent much larger spaces than the grid cells, which enable them to support navigational behaviors. Both self-organizing maps amplify and learn to categorize the most frequent and energetic co-occurrences of their inputs. The current results build upon a previous rate-based model of grid and place cell learning, and thus illustrate a general method for converting rate-based adaptive neural models, without the loss of any of their analog properties, into models whose cells obey spiking dynamics. New properties of the spiking GridPlaceMap model include the appearance of theta band modulation. The spiking model also opens a path for implementation in brain-emulating nanochips comprised of networks of noisy spiking neurons with multiple-level adaptive weights for controlling autonomous adaptive robots capable of spatial navigation.     

Areal Distributions of Cortical Neurons Projecting to Different Levels of the Caudal Brain Stem and Spinal Cord in Rats

Distributions of corticospinal and corticobulbar neurons were revealed by tetramethylbenzidine (TMB) processing after injections of wheatgerm agglutinin conjugated to horseradish peroxidase (WGA:HRP) into the cervical or lumbar enlargements of the spinal cord, or medullary or pontine levels of the brain stem. Sections reacted for cytochrome oxidase (CO) allowed patterns of labeled neurons to be related to the details of the body surface map in the first somatosensory cortical area (SI). The results indicate that a number of cortical areas project to these subcortical levels: (1) Projection neurons in granular SI formed a clear somatotopic pattern. The hindpaw region projected to the lumbar enlargement, the forepaw region to the cervical enlargement, the whisker pad field to the lower medulla, and the more rostral face region to more rostral brain stem levels. (2) Each zone of labeled neurons in SI extended into adjacent dysgranular somatosensory cortex, forming a second somatotopic pattern of projection neurons. (3) A somatotopic pattern of projection neurons in primary motor cortex (MI) paralleled SI in mediolateral sequence corresponding to the hindlimb, forelimb, and face. (4) A weak somatotopic pattern of projection neurons was suggested in medial agranular cortex (Ag_m), indicating a premotor field with a rostromedial-to-caudolateral representation of hindlimb, forelimb, and face. (5) A somatotopic pattern of projection neurons representing the foot to face in a mediolateral sequence was observed in medial parietal cortex (PM) located between SI and area 17. (6) In the second somatosensory cortical area (SII), neurons projecting to the brain stem were immediately adjacent caudolaterally to the barrel field of SI, whereas neurons projecting to the upper spinal cord were more lateral. No projection neurons in this region were labeled by the injections in the lower spinal cord. (7) Other foci of projection neurons for the face and forelimb were located rostral to SII, providing evidence for a parietal ventral area (PV) in perirhinal cortex (PR) lateral to SI, and in cortex between SII and PM. None of these regions, which may be higher-order somatosensory areas, contained labeled neurons after injections in the lower spinal cord. Thus, more cortical fields directly influence brain stem and spinal cord levels related to sensory and motor functions of the face and forepaw than the hindlimb.

The termination patterns of corticospinal and corticobulbar projections were studied in other rats with injections of WGA:HRP in SI. Injections in lateral SI representing the face produced dense terminal label in the contralateral trigeminal complex. Injections in cortex devoted to the forelimb and forepaw labeled the contralateral cuneate nucleus and parts of the dorsal horn of the spinal cord. The cortical injections also demonstrated interconnections of parts of SI with some of the other regions of cortex with projections to the spinal cord, and provided further evidence for the existence of PV in rats.     

Investigating Glutamatergic Mechanism in Attention and Impulse Control Using Rats in a Modified 5-Choice Serial Reaction Time Task

The 5-choice serial reaction time task (5CSRTT) has been widely used to study attention and impulse control in rodents. In order to mimic cognitive impairments in psychiatry, one approach has been to use acute administration of NMDA antagonists. This disruption in glutamatergic transmission leads to impairments in accuracy, omissions, and premature responses although findings have been inconsistent. In this study, we further investigated glutamatergic mechanisms using a novel version of the 5CSRTT, which we have previously shown to be more sensitive to cognitive enhancers. We first investigated the effects of systemic treatment with NMDA antagonists. We also carried out a preliminary investigation using targeted medial prefrontal cortex infusions of a NMDA antagonist (MK801), mGluR2/3 antagonist ({"type":"entrez-nucleotide","attrs":{"text":"LY341495","term_id":"1257705759","term_text":"LY341495"}}LY341495), and mGluR7 negative allosteric modulator (MMPIP). Acute systemic administration of the different NMDA antagonists had no specific effects on accuracy. At higher doses PCP, ketamine, and memantine, increased omissions and affected other measures suggesting a general disruption in task performance. Only MK801 increased premature responses, and reduced omissions at lower doses suggesting stimulant like effects. None of the NMDA antagonists affected accuracy or any other measures when tested using a short stimulus challenge. Infusions of MK801 had no effect on accuracy but increased premature responses following infralimbic, but not prelimbic infusion. {"type":"entrez-nucleotide","attrs":{"text":"LY341495","term_id":"1257705759","term_text":"LY341495"}}LY341495 had no effects in either brain region but a decrease in accuracy was observed following prelimbic infusion of MMPIP. Contrary to our hypothesis, disruptions to glutamate transmission using NMDA antagonists did not induce any clear deficits in accuracy in this modified version of the 5CSRTT. We also found that the profile of effects for MK801 differed from those observed with PCP, ketamine, and memantine. The effects of MK801 in the infralimbic cortex add to the literature indicating this brain region and glutamate play an important role in impulse control.     

Direct Evidence for Calpain Involvement in Apoptotic Death of Neurons in Spinal Cord Injury in Rats and Neuroprotection with Calpain Inhibitor

To demonstrate calpain involvement in neurodegeneration in rat spinal cord injury (SCI), we examined SCI segments for DNA fragmentation, neurons for calpain overexpression, neuronal death, and neuroprotection with calpain inhibitor (E-64-d). After the induction of SCI (40 g cm force) on T12, rats were treated within 15 min with vehicle (DMSO) or E-64-d. Sham animals underwent laminectomy only. Animals were sacrificed at 24 h, and five 1-cm long spinal cord segments were collected: two rostral (S1 and S2), one lesion (S3), and two caudal segments (S4 and S5). Agarose gel electrophoresis of DNA samples isolated from the SCI segments showed both random and internucleosomal DNA fragmentation indicating occurrence of necrosis as well as apoptosis mostly in the lesion, moderately in caudal, and slightly in rostral segments from SCI rats. Treatment of SCI rats with E-64-d (1 mg/kg) reduced DNA fragmentation in all segments. The lesion and adjacent caudal segments (S3 and S4) were further investigated by in situ double-immunofluorescent labelings that showed increase in calpain expression in neurons in SCI rats and decrease in calpain expression in SCI rats treated with E-64-d. In situ combined TUNEL and double-immunofluorescent labelings directly detected co-localization of neuronal death and calpain overexpressin in SCI rats treated with only vehicle while attenuation of neuronal death in SCI rats treated with E-64-d. Previous studies from our laboratory indirectly showed neuroprotective effect of E-64-d in SCI rats. Our current results provide direct in situ evidence for calpain involvement in neuronal death and neuroprotective efficacy of E-64-d in lesion and penumbra in SCI rats. Special issue in honor of Naren Banik.