Biomedical subjects

Michael E Hasselmo

Publications and source records attributed to Michael E Hasselmo.

At least 19 recordsLinked to original sources

PubMed2006

Modeling of context-dependent retrieval in hippocampal region CA1: implications for cognitive function in schizophrenia.

The symptoms of schizophrenia may be associated with reductions in NMDA receptor (NMDAR) function. This is suggested by the psychotomimetic effects of NMDA antagonists, the ameliorative effects of NMDAR indirect agonists, elevated levels of the NMDA antagonist N-acetyl-aspartyl-glutamate (NAAG) in schizophrenic brain, and findings from recent genetic studies. However, the link between reduced NMDAR function and the behavioral features of schizophrenics has not been made explicit. Here we present a network simulation of hippocampal function, focused on retrieval of verbal stimuli in human memory tasks. Specifically, we trained a computational model of the hippocampal complex to perform a context-dependent paired associate task, a free recall task with category clustering, and the transitive inference (TI) task. In this network, direct perforant pathway input from entorhinal cortex to region CA1 provides the basis for semantic context cueing during initial encoding and retrieval, allowing selective retrieval on the basis of category cues. Alterations in the magnitude of this direct perforant pathway input to region CA1 causes impairments in use of organizational strategies for memory, accounting for specific features of memory dysfunction in schizophrenics and in normals treated with ketamine. This model provides a theoretical link between cellular physiological changes and specific cognitive symptoms. As such, it can shed light on the etiology of schizophrenia in a fundamental way, and also holds the promise of pointing the way to more effective treatments.

Brain Mapping↗

PubMed2006

First-in-first-out item replacement in a model of short-term memory based on persistent spiking.

Persistent neuronal firing has been modeled in relation to observed brain rhythms, especially to theta oscillations recorded in behaving animals. Models of short-term memory that are based on such persistent firing properties of specific neurons can meet the requirements of spike-timing-dependent potentiation of synaptic strengths during the encoding of a temporal sequence of spike patterns. We show that such a spiking buffer can be simulated with integrate-and-fire neurons that include a leak current even when different numbers of spikes represent successive items. We propose a mechanism that successfully replaces items in the buffer in first-in-first-out (FIFO) order when the distribution of spike density in a theta cycle is asymmetric, as found in experimental data. We predict effects on the function and capacity of the buffer model caused by changes in modeled theta cycle duration, the timing of input to the buffer, the strength of recurrent inhibition, and the strength and timing of after-hyperpolarization and after-depolarization (ADP). Shifts of input timing or changes in ADP parameters can enable the reverse-order buffering of items, with FIFO replacement in a full buffer. As noise increases, the simulated buffer provides robust output that may underlie episodic encoding.

Algorithms↗

PubMed2006

Mechanisms underlying working memory for novel information.

In this Opinion article we describe a theory that the brain mechanisms underlying working memory for novel information include a buffer in parahippocampal cortices. Computational modeling indicates that mechanisms for maintaining novel information in working memory could differ from mechanisms for maintaining familiar information. Electrophysiological data suggest that the buffer for novel information depends on acetylcholine. Acetylcholine activates single-cell mechanisms that underlie persistent spiking of neurons in the absence of synaptic transmission, allowing maintenance of information without prior synaptic modification. fMRI studies and lesion studies suggest that parahippocampal regions mediate working memory for novel stimuli, and the effects of cholinergic blockade impair this function. These intrinsic mechanisms in parahippocampal cortices provide an important alternative to theories of working memory based on recurrent synaptic excitation.

Acetylcholine↗

PubMed2006

The role of acetylcholine in learning and memory.

Pharmacological data clearly indicate that both muscarinic and nicotinic acetylcholine receptors have a role in the encoding of new memories. Localized lesions and antagonist infusions demonstrate the anatomical locus of these cholinergic effects, and computational modeling links the function of cholinergic modulation to specific cellular effects within these regions. Acetylcholine has been shown to increase the strength of afferent input relative to feedback, to contribute to theta rhythm oscillations, activate intrinsic mechanisms for persistent spiking, and increase the modification of synapses. These effects might enhance different types of encoding in different cortical structures. In particular, the effects in entorhinal and perirhinal cortex and hippocampus might be important for encoding new episodic memories.

Acetylcholine↗

PubMed2006

Gradual translocation of spatial correlates of neuronal firing in the hippocampus toward prospective reward locations.

In a continuous T-maze alternation task, CA1 complex-spike neurons in the hippocampus differentially fire as the rat traverses overlapping segments of the maze (i.e., the stem) repeatedly via alternate routes. The temporal dynamics of this phenomenon were further investigated in the current study. Rats learned the alternation task from the first day of acquisition and the differential firing pattern in the stem was observed accordingly. More importantly, we report a phenomenon in which spatial correlates of CA1 neuronal ensembles gradually changed from their original firing locations, shifting toward prospective goal locations in the continuous T-maze alternation task. The relative locations of simultaneously recorded firing fields, however, were preserved within the ensemble spatial representation during this shifting. The within-session shifts in preferred firing locations in the absence of any changes in the environment suggest that certain cognitive factors can significantly alter the location-bound coding scheme of hippocampal neurons.

Animals↗

PubMed2006

Hippocampal CA1 spiking during encoding and retrieval: relation to theta phase.

The hippocampal theta rhythm is a prominent oscillation in the field potential observed throughout the hippocampus as a rat investigates stimuli in the environment. A recent computational model [Hasselmo, M. E., Bodelon, C., & Wyble, B. P. (2002a). A proposed function for hippocampal theta rhythm: separate phases of encoding and retrieval enhance reversal of prior learning. Neural Computation, 14, 793-817. Neuromodulation, theta rhythm and rat spatial navigation. Neural Networks, 15, 689-707] suggested that the theta rhythm allows the hippocampal formation to alternate rapidly between conditions that promote memory encoding (strong synaptic input from entorhinal cortex to areas CA3 and CA1) and conditions that promote memory retrieval (strong synaptic input from CA3 to CA1). That model predicted that the preferred theta phase of CA1 spiking should differ for information being encoded versus information being retrieved. In the present study, the spiking activity of CA1 pyramidal cells was recorded while rats performed either an odor-cued delayed nonmatch-to-sample recognition memory test or an object recognition memory task based on the animal's spontaneous preference for novelty. In the test period of both tasks, the preferred theta phase exhibited by CA1 pyramidal cells differed between moments when the rat inspected repeated (match) and non-repeated (nonmatch) items. Also in the present study, additional modeling work extended the previous model to address the mean phase of CA1 spiking associated with stimuli inducing varying levels of retrieval relative to encoding, ranging from novel nonmatch stimuli with no retrieval to highly familiar repeated stimuli with extensive retrieval. The modeling results obtained here demonstrated that the experimentally observed phase differences are consistent with different levels of CA3 synaptic input to CA1 during recognition of repeated items.

Animals↗

PubMed2006

Mechanism of graded persistent cellular activity of entorhinal cortex layer v neurons.

Working memory is an emergent property of neuronal networks, but its cellular basis remains elusive. Recent data show that principal neurons of the entorhinal cortex display persistent firing at graded firing rates that can be shifted up or down in response to brief excitatory or inhibitory stimuli. Here, we present a model of a potential mechanism for graded firing. Our multicompartmental model provides stable plateau firing generated by a nonspecific calcium-sensitive cationic (CAN) current. Sustained firing is insensitive to small variations in Ca2+ concentration in a neutral zone. However, both high and low Ca2+ levels alter firing rates. Specifically, increases in persistent firing rate are triggered only during high levels of calcium, while decreases in rate occur in the presence of low levels of calcium. The model is consistent with detailed experimental observations and provides a mechanism for maintenance of memory-related activity in individual neurons.

Action Potentials↗

PubMed2006

Difference in time course of modulation of synaptic transmission by group II versus group III metabotropic glutamate receptors in region CA1 of the hippocampus.

We investigated the time course of modulation of synaptic transmission by group II and group III metabotropic glutamate receptors in region CA1 of the hippocampus. In the presence of 50 microM picrotoxin, pressure pulse application of 1 mM glutamate resulted in a fast onset of suppression of synaptic transmission in stratum lacunosum moleculare and a slower onset of suppression in stratum radiatum, with both effects returning to baseline over the course of several minutes. Application of 50 microM of the group II agonist (2R,4R)-APDC in stratum lacunosum moleculare resulted in the same fast onset of suppression while having no effect in stratum radiatum. Pressure pulse application of 100 microM DL-AP4 in stratum lacunosum moleculare and stratum radiatum resulted in a much slower onset of suppression of synaptic transmission than (2R,4R)-APDC. Suppression by (2R,4R)-APDC was accompanied by a rapid enhancement of paired pulse facilitation, indicative of a presynaptic mechanism. This demonstrates that activation of group II mGluRs in the hippocampus causes a fast onset of suppression in stratum lacunosum moleculare, while activation of group III mGluRs causes a slower onset of suppression. The difference in time course for group II vs. group III mGluRs suggests a different functional role, with group II playing a potential role in making synapses act as low pass filters.

Animals↗

PubMed2006

An analysis of the mean theta phase of population activity in a model of hippocampal region CA1.

In a recent study, Manns et al. (2007) showed that CA1 population spiking activity differs in mean phase between conditions of exposure to stimuli of varying levels of familiarity. Here, we provide an analysis of a computational model of the hippocampus from Hasselmo et al. (2002) to examine how an animal's history of exposures to stimuli affects CA1 population activity. We show how the model can reproduce the major findings from the study by Manns et al. Specifically, we show that differences in direction and magnitude of the mean phase of population activity between two stimuli in the model depend on the order of presentation of the stimuli and the duration of exposure during each presentation. The analyses also reveal that the model's learning rule results in stability and normalization of synaptic weights and show how dysfunction of neuromodulatory systems might lead to epileptic or amnestic type conditions.

Action Potentials↗

PubMed2005

Hippocampal mechanisms for the context-dependent retrieval of episodes.

Behaviors ranging from delivering newspapers to waiting tables depend on remembering previous episodes to avoid incorrect repetition. Physiologically, this requires mechanisms for long-term storage and selective retrieval of episodes based on the time of occurrence, despite variable intervals and similarity of events in a familiar environment. Here, this process has been modeled based on the physiological properties of the hippocampal formation, including mechanisms for sustained activity in entorhinal cortex and theta rhythm oscillations in hippocampal subregions. The model simulates the context-sensitive firing properties of hippocampal neurons including trial-specific firing during spatial alternation and trial by trial changes in theta phase precession on a linear track. This activity is used to guide behavior, and lesions of the hippocampal network impair memory-guided behavior. The model links data at the cellular level to behavior at the systems level, describing a physiologically plausible mechanism for the brain to recall a given episode which occurred at a specific place and time.

Animals↗

PubMed2005

Cholinergic deafferentation of the entorhinal cortex in rats impairs encoding of novel but not familiar stimuli in a delayed nonmatch-to-sample task.

Acetylcholine may regulate working memory for novel stimuli by activating intrinsic mechanisms for sustained spiking in entorhinal cortical neurons, which have been demonstrated in slice preparations of the entorhinal cortex. Computational modeling demonstrates that loss of the cholinergic activation of intrinsic mechanisms for sustained activity could selectively impair working memory for novel stimuli, whereas working memory for familiar stimuli could be maintained because of previously modified synapses. Blockade of muscarinic cholinergic receptors and selective cholinergic lesions has been shown to impair encoding in delayed matching tasks. However, previous studies have not compared explicitly the role of cholinergic modulation in working memory for novel versus familiar stimuli. Here, we show that lesions of the cholinergic innervation of the entorhinal cortex selectively impair delayed nonmatch to sample performance for novel odors, whereas delayed nonmatch to sample for familiar odors is spared. This indicates an important role for cholinergic innervation of the entorhinal cortex in working memory for novel stimuli.

Afferent Pathways↗

PubMed2005

Scopolamine reduces persistent activity related to long-term encoding in the parahippocampal gyrus during delayed matching in humans.

Recent computational modeling and slice physiology studies have suggested that long-term encoding may depend on sustained spiking during brief memory delays in parahippocampal neurons, and that this persistent spiking activity is modulated by effects of acetylcholine at muscarinic receptors. Our recent functional magnetic resonance imaging (fMRI) study has shown that sustained parahippocampal delay period activity during delayed match-to-sample performance in healthy young individuals predicted subsequent memory of visual stimuli on a recognition memory assessment 20 min later (Schon et al., 2004). The current study combined this fMRI paradigm with a pharmacological manipulation to test whether this long-term encoding-related delay activity is reduced in subjects who receive the muscarinic cholinergic antagonist scopolamine before fMRI scanning. Subsequent memory was predicted by sustained activity during brief memory delays bilaterally in the perirhinal/entorhinal cortex, in the right posterior parahippocampal and mid-fusiform gyri, and in the hippocampal body in healthy young individuals without a scopolamine challenge. This activity was reduced in subjects receiving scopolamine. The results are consistent with computational modeling data and behavioral pharmacological studies, suggesting that long-term encoding-related activity may be reduced if cholinergic receptors are blocked by scopolamine.

Analysis of Variance↗

PubMed2005

Less is more: how reduced activity reflects stronger recognition.

The mechanisms of recognition involve reductions of activity in the medial temporal lobe. This preview discusses recent fMRI and MEG data from Gonsalves et al. (this issue of Neuron) that provide some of the strongest evidence to date demonstrating that reduced medial temporal activity is correlated with stronger recognition of items in humans. This result provides an important test of theories of recognition memory function based on previous neuroimaging and unit recording data.

Brain Mapping↗

PubMed2005

An integrate-and-fire model of prefrontal cortex neuronal activity during performance of goal-directed decision making.

The orbital frontal cortex appears to be involved in learning the rules of goal-directed behavior necessary to perform the correct actions based on perception to accomplish different tasks. The activity of orbitofrontal neurons changes dependent upon the specific task or goal involved, but the functional role of this activity in performance of specific tasks has not been fully determined. Here we present a model of prefrontal cortex function using networks of integrate-and-fire neurons arranged in minicolumns. This network model forms associations between representations of sensory input and motor actions, and uses these associations to guide goal-directed behavior. The selection of goal-directed actions involves convergence of the spread of activity from the goal representation with the spread of activity from the current state. This spiking network model provides a biological implementation of the action selection process used in reinforcement learning theory. The spiking activity shows properties similar to recordings of orbitofrontal neurons during task performance.

Action Potentials↗

PubMed2005

Encoding and retrieval in the CA3 region of the hippocampus: a model of theta-phase separation.

Past research conducted by Hasselmo et al. in 2002 suggests that some fundamental tasks are better accomplished if memories are encoded and recovered during different parts of the theta cycle. A model of the CA3 subfield of the hippocampus is presented, using biophysical representations of the major cell types including pyramidal cells and two types of interneurons. Inputs to the network come from the septum and the entorhinal cortex (directly and by the dentate gyrus). A mechanism for parsing the theta rhythm into two epochs is proposed and simulated: in the first half, the strong, proximal input from the dentate to a subset of CA3 pyramidal cells and coincident, direct input from the entorhinal cortex to other pyramidal cells creates an environment for strengthening synapses between cells, thus encoding information. During the second half of theta, cueing signals from the entorhinal cortex, by the dentate, activate previously strengthened synapses, retrieving memories. Slow inhibitory neurons (O-LM cells) play a role in the disambiguation during retrieval. We compare and contrast our computational results with existing experimental data and other contemporary models.

Animals↗

PubMed2005

Medial prefrontal cortex cells show dynamic modulation with the hippocampal theta rhythm dependent on behavior.

Both the hippocampus and the medial prefrontal cortex are essential for successful performance in learning- and memory-related tasks. Within the hippocampus the theta rhythm plays an integral role in the timing of action potentials of hippocampal neurons responding to elements of any given task. Medial prefrontal cortex (mPFC) neurons display firing rate changes to specific facets of behavioral tasks (Jung et al., 1998. Cereb Cortex 8:437--450). We recorded units in the mPFC and field potentials in the hippocampus to determine whether behaviorally correlated mPFC cells fired with phase relationships to the hippocampal theta rhythm. In two different behavioral tasks (running a linear track and foraging in two distinct environments) we found mPFC cells that alternated between theta entrained firing and nonphasic firing depending on the ongoing behavior, while other cells were modulated during all conditions in both tasks. The majority of the mPFC cells with a significant correlation of firing rate changes with behavior were entrained to hippocampal theta. Cells that fired to specific events during only one direction of running were predisposed to theta modulation only in that direction. mPFC neurons have the capability to respond to behaviorally relevant elements by dynamically alternating between hippocampal theta entrained and nonphasic firing.

Action Potentials↗

PubMed2005

What is the function of hippocampal theta rhythm?--Linking behavioral data to phasic properties of field potential and unit recording data.

The extensive physiological data on hippocampal theta rhythm provide an opportunity to evaluate hypotheses about the role of theta rhythm for hippocampal network function. Computational models based on these hypotheses help to link behavioral data with physiological measurements of different variables during theta rhythm. This paper reviews work on network models in which theta rhythm contributes to the following functions: (1) separating the dynamics of encoding and retrieval, (2) enhancing the context-dependent retrieval of sequences, (3) buffering of novel information in entorhinal cortex (EC) for episodic encoding, and (4) timing interactions between prefrontal cortex and hippocampus for memory-guided action selection. Modeling shows how these functional mechanisms are related to physiological data from the hippocampal formation, including (1) the phase relationships of synaptic currents during theta rhythm measured by current source density analysis of electroencephalographic data from region CA1 and dentate gyrus, (2) the timing of action potentials, including the theta phase precession of single place cells during running on a linear track, the context-dependent changes in theta phase precession across trials on each day, and the context-dependent firing properties of hippocampal neurons in spatial alternation (e.g., "splitter cells"), (3) the cholinergic regulation of sustained activity in entorhinal cortical neurons, and (4) the phasic timing of prefrontal cortical neurons relative to hippocampal theta rhythm.

Action Potentials↗

PubMed2005

Unraveling the attentional functions of cortical cholinergic inputs: interactions between signal-driven and cognitive modulation of signal detection.

Neurophysiological studies demonstrated that increases in cholinergic transmission in sensory areas enhance the cortical processing of thalamic inputs. Cholinergic activity also suppresses the retrieval of internal associations, thereby further promoting sensory input processing. Behavioral studies documented the role of cortical cholinergic inputs in attentional functions and capacities by demonstrating, for example, that the integrity of the cortical cholinergic input system is necessary for attentional performance, and that the activity of cortical cholinergic inputs is selectively enhanced during attentional performance. This review aims at integrating the neurophysiological and behavioral evidence on the functions of cortical cholinergic inputs and hypothesizes that the cortical cholinergic input system generally acts to optimize the processing of signals in attention-demanding contexts. Such signals 'recruit', via activation of basal forebrain corticopetal cholinergic projections, the cortical attention systems and thereby amplify the processing of attention-demanding signals (termed 'signal-driven cholinergic modulation of detection'). The activity of corticopetal cholinergic projections is also modulated by direct prefrontal projections to the basal forebrain and, indirectly, to cholinergic terminals elsewhere in the cortex; thus, cortical cholinergic inputs are also involved in the mediation of top-down effects, such as the knowledge-based augmentation of detection (see Footnote 1) of signals and the filtering of irrelevant information (termed 'cognitive cholinergic modulation of detection'). Thus, depending on the quality of signals and task characteristics, cortical cholinergic activity reflects the combined effects of signal-driven and cognitive modulation of detection. This hypothesis begins to explain signal intensity or duration-dependent performance in attention tasks, the distinct effects of cortex-wide versus prefrontal cholinergic deafferentation on attention performance, and it generates specific predictions concerning cortical acetylcholine (ACh) release in attention task-performing animals. Finally, the consequences of abnormalities in the regulation of cortical cholinergic inputs for the manifestation of the symptoms of major neuropsychiatric disorders are conceptualized in terms of dysregulation in the signal-driven and cognitive cholinergic modulation of detection processes.

Acetylcholine↗