Cholinergic suppression of glutamatergic synaptic transmission in hippocampal region CA3 exhibits laminar selectivity: Implication for hippocampal network dynamics.

Acetylcholine may help set the dynamics within neural systems to facilitate the learning of new information. Neural models have shown that if new information is encoded at the same time as retrieval of existing information that is already stored, the memories will interfere with each other. Structures such as the hippocampus have a distinct laminar organization of inputs that allows this hypothesis to be tested. In region CA1 of the rat (Sprague Dawley) hippocampus, the cholinergic agonist carbachol (CCh) suppresses transmission in stratum radiatum (SR), at synapses of the Schaffer collateral projection from CA3, while having lesser effects in stratum lacunosum-moleculare (SLM), the perforant path projection from entorhinal cortex (Hasselmo and Schnell, 1994). The current research extends support of this selectivity by demonstrating laminar effects in region CA3. CCh caused significantly greater suppression in SR than in SLM at low concentrations, while the difference in suppression was not significant at higher concentrations. Differences in paired-pulse facilitation suggest presynaptic inhibition substantially contributes to the suppression and is highly concentration and stratum dependent. This selective suppression of the recurrent excitation would be appropriate to set CA3 dynamics to prevent runaway modification of the synapses of excitatory recurrent collaterals by reducing the influence of previously stored associations and allowing incoming information from the perforant path to have a predominant influence on neural activity.

Acetylcholine and memory.

Acetylcholine may set the dynamics of cortical networks to those appropriate for learning of new information, while decreased cholinergic modulation may set the appropriate dynamics for recall. In slice preparations of the olfactory cortex, acetylcholine selectively suppresses intrinsic but not afferent fiber synaptic transmission, while decreasing the adaptation of pyramidal cells. In biologically realistic models of this region, the selective suppression of synaptic transmission prevents recall of previously learned memories from interfering with the learning of new memories, while the decrease in adaptation enhances the response to afferent input and the modification of synapses. This theoretical framework may serve to guide future studies linking neuromodulators to cortical memory function.

The hippocampus as an associator of discontiguous events.

The hippocampus has long been thought to be an important cortical region for associative learning and memory. After several decades of experimental and theoretical studies, a picture is emerging slowly of the generic types of learning tasks that this neural structure might be essential for solving. Recently, there have been attempts to unify electrophysiological and behavioral observations from rodents performing spatial learning tasks with data from primates performing various tests of conditional and discrimination learning. Most of these theoretical frameworks have rested primarily on behavioral observations. Complementing these perspectives,we ask the question: given certain physiological constraints at the neuronal and cortical level, what class of learning problems is the hippocampus, in particular, most suited to solve? From a computational point of view, we argue that this structure is involved most critically in learning and memory tasks in which discontiguous items must be associated, in terms of their temporal or spatial positioning, or both.

Neural models of memory.

Neural models assist in characterizing the processes carried out by cortical and hippocampal memory circuits. Recent models of memory have addressed issues including recognition and recall dynamics, sequences of activity as the unit of storage, and consolidation of intermediate-term episodic memory into long-term memory.

Cholinergic modulation of cortical function.

Extensive physiological research has demonstrated a number of common effects of acetylcholine within cortical structures, including the hippocampus, piriform cortex, and neocortex (Hasselmo, 1995, 1999). This article will provide a description of how the different physiological effects of acetylcholine could interact to alter specific functional properties of the cortex. The physiological effects of acetylcholine serve to enhance the influence of feed- forward afferent input to the cortex while decreasing background activity by suppressing excitatory feedback connections within cortical circuits. By enhancing the response to sensory input, high levels of acetylcholine enhance attention to sensory stimuli in the environment and enhance encoding of memory for specific stimuli. Interference from prior memory is reduced by suppressing synapses modified by prior learning (Sevilla et al., 2002; Linster et al., 2003).

Gamma frequency-range abnormalities to auditory stimulation in schizophrenia.

BACKGROUND: Basic science studies at the neuronal systems level have indicated that gamma-range (30-50 Hz) neural synchronization may be a key mechanism of information processing in neural networks, reflecting integration of various features of an object. Furthermore, gamma-range synchronization is thought to depend on the glutamatergically mediated interplay between excitatory projection neurons and inhibitory neurons utilizing gamma-aminobutyric acid (GABA), which postmortem studies suggest may be abnormal in schizophrenia. We therefore tested whether auditory neural networks in patients with schizophrenia could support gamma-range synchronization. METHODS: Synchronization of the electroencephalogram (EEG) to different rates (20-40 Hz) of auditory stimulation was recorded from 15 patients with schizophrenia and 15 sex-, age-, and handedness-matched control subjects. The EEG power at each stimulation frequency was compared between groups. The time course of the phase relationship between each stimulus and EEG peak was also evaluated for gamma-range (40 Hz) stimulation. RESULTS: Schizophrenic patients showed reduced EEG power at 40 Hz, but not at lower frequencies of stimulation. In addition, schizophrenic patients showed delayed onset of phase synchronization and delayed desynchronization to the click train. CONCLUSIONS: These data provide new information on selective deficits in early-stage sensory processing in schizophrenia, a failure to support the entrainment of intrinsic gamma-frequency oscillators. The reduced EEG power at 40 Hz in schizophrenic patients may reflect a dysfunction of the recurrent inhibitory drive on auditory neural networks.

Muscarinic cholinergic neuromodulation reduces proactive interference between stored odor memories during associative learning in rats.

Previous electrophysiological studies and computational modeling suggest the hypothesis that cholinergic neuromodulation may reduce olfactory associative interference during learning (M. E. Hasselmo, B. P. Anderson, & J. M. Bower, 1992; M. E. Hasselmo & J. M. Bower, 1993). These results provide behavioral evidence supporting this hypothesis. A simultaneous discrimination task required learning a baseline odor pair (A+B-) and then, under the influence of scopolamine, a novel odor pair (A-C+) with an overlapping component (A) versus a novel odor pair (D+E-) with no overlapping component. As predicted by the model, rats that received scopolamine (0.50 and 0.25 mg/kg) were more impaired at acquiring overlapping than nonoverlapping odor pairs relative to their performance under normal saline or methylscopolamine. These results support the prediction that the physiological effects of acetylcholine can reduce interference between stored odor memories during associative learning.

Selective loss of cholinergic neurons projecting to the olfactory system increases perceptual generalization between similar, but not dissimilar, odorants.

The neuromodulator acetylcholine is thought to modulate information processing in the olfactory system. The authors used 192 IgG-saporin, a lesioning agent selective for basal forebrain cholinergic neurons, to determine whether selective lesions of cholinergic neurons projecting to the olfactory bulb and cortex affect odor perception in rats. Lesioned and sham-operated rats were tested in an olfactory generalization paradigm with sets of chemically related odorants (n-aliphatic aldehydes, acids, and alcohols). Lesioned rats generalized more between chemically similar odorants but did not differ from controls in their response to chemically unrelated odorants or in acquisition of the conditioned odor. Results show that cholinergic inputs to the olfactory system influence perceptual qualities of odorants and confirm predictions made by computational models of this system.

Contribution of the cholinergic basal forebrain to proactive interference from stored odor memories during associative learning in rats.

E. De Rosa and M. E. Hasselmo (2000) demonstrated that 0.25 mg/kg scopolamine (SCOP) selectively increased proactive interference (PI) from stored odor memories during learning. In the present study, rats with bilateral cholinergic lesions limited to the horizontal limb of the diagonal band of Broca, made with 192 IgG-saporin, were not impaired in acquiring the same olfactory discrimination task relative to control rats. Rats with bilateral 192 IgG-saporin lesions to all basal forebrain cholinergic nuclei (BF) also showed no impairment in acquisition of this task. However, the BF-saporin rats were hypersensitive to oxotremorine-induced hypothermia and demonstrated an increased sensitivity to PI following a low dose of SCOP (0.125 mg/kg) relative to control rats. The results suggest that weaker cholinergic modulation after cholinergic BF lesions makes the system more sensitive to PI during blockade of the remaining cholinergic elements.

Computational modeling of entorhinal cortex.

Computational modeling provides a means for linking the physiological and anatomical characteristics of entorhinal cortex at a cellular level to the functional role of this region in behavior. We have developed detailed simulations of entorhinal cortical neurons and networks, with an emphasis on the role of acetylcholine in entorhinal cortical function. Computational modeling suggests that when acetylcholine levels are high, this sets appropriate dynamics for the storage of stimuli during performance of delayed matching tasks. In particular, acetylcholine activates a calcium-sensitive nonspecific cation current which provides an intrinsic cellular mechanism which could maintain neuronal activity across a delay period. Simulations demonstrate how this phenomena could underlie entorhinal cortex delay activity as described in previous unit recordings. Acetylcholine also induces theta rhythm oscillations which may be appropriate for timing of afferent input to be encoded in hippocampus and for extraction of individual stored sequences from multiple stored sequences. Lower levels of acetylcholine may allow sharp wave dynamics which can reactivate associations encoded in hippocampus and drive the formation of additional traces in hippocampus and entorhinal cortex during consolidation.

Neuromodulation and cortical function: modeling the physiological basis of behavior.

Neuromodulators including acetylcholine, norepinephrine, serotonin, dopamine and a range of peptides alter the processing characteristics of cortical networks through effects on excitatory and inhibitory synaptic transmission, on the adaptation of cortical pyramidal cells, on membrane potential, on the rate of synaptic modification, and on other cortical parameters. Computational models of self-organization and associative memory function in cortical structures such as the hippocampus, piriform cortex and neocortex provide a theoretical framework in which the role of these neuromodulatory effects can be analyzed. Neuromodulators such as acetylcholine and norepinephrine appear to enhance the influence of synapses from afferent fibers arising outside the cortex relative to the synapses of intrinsic and association fibers arising from other cortical pyramidal cells. This provides a continuum between a predominant influence of external stimulation to a predominant influence of internal recall (extrinsic vs. intrinsic). Modulatory influence along this continuum may underlie effects described in terms of learning and memory, signal to noise ratio, and attention.

Effect of long term baclofen treatment on recognition memory and novelty detection.

We studied the effect of long term baclofen treatment on recognition memory and novelty detection in rats using a habituation paradigm in an open field setting. Rats pretreated with 3 weeks' daily baclofen injection (0, 2 and 5 mg/kg) were tested in four 10 min sessions (familiarization session and three testing sessions: S1, S2 and S3) with 10-min intersession intervals. During S1, S2 and S3, rats were repeatedly exposed to the same two odor stimuli. During S3, for half of the rats in each treatment group, the spatial locations of the two stimuli were switched (Change) and for the other half the stimuli were replaced in the same locations (No Change). Two habituation scores were measured for each subject: H1 = N1 - N2; H2 = N2 - N3 (Ni the number of contacts made during Si). Baclofen at the highest dose (5 mg/kg) reduced the amount of habituation between S1 and S2 (H1) and increased responses to novel spatial arrangement, measured as the difference between H2 for the No-Change and Change groups. These results suggest a simultaneous impairment of recognition memory and enhancement of spatial novelty detection.

Free recall and recognition in a network model of the hippocampus: simulating effects of scopolamine on human memory function.

Free recall and recognition are simulated in a network model of the hippocampal formation, incorporating simplified simulations of neurons, synaptic connections, and the effects of acetylcholine. Simulations focus on modeling the effects of the acetylcholine receptor blocker scopolamine on human memory. Systemic administration of scopolamine is modeled by blockade of the cellular effects of acetylcholine in the model, resulting in memory impairments replicating data from studies on human subjects. This blockade of cholinergic effects impairs the encoding of new input patterns (as measured by delayed free recall), but does not impair the delayed free recall of input patterns learned before the blockade. The impairment is selective to the free recall but not the recognition of items encoded under the influence of scopolamine. In the model, scopolamine blocks strengthening of recurrent connections in region CA3 to form attractor states for new items (encoding impaired) but allows recurrent excitation to drive the network into previously stored attractor states (retrieval spared). Neuron populations representing items (individual words) have weaker recurrent connections than neuron populations representing experimental context. When scopolamine further weakens the strength of recurrent connections it selectively prevents the subsequent reactivation of item attractor states by context input (impaired free recall) without impairing the subsequent reactivation of context attractor states by item input (spared recognition). This asymmetry in the strength of attractor states also allows simulation of the list-strength effect for free recall but not recognition. Simulation of a paired associate learning paradigm predicts that scopolamine should greatly enhance proactive interference due to retrieval of previously encoded associations during storage of new associations.

Suppression of synaptic transmission may allow combination of associative feedback and self-organizing feedforward connections in the neocortex.

Selective suppression of synaptic transmission during learning is proposed as a physiological mechanism for combining associative memory function at feedback synapses with self-organization of feedforward synapses in neocortical structures. A computational model demonstrates how selective suppression of feedback transmission allows this combination of synaptic function. During learning, sensory stimuli and the desired response are simultaneously presented as input to the network. Feedforward connections form self-organized representations of input, while suppressed feedback connections learn the transpose of the feedforward connectivity. During recall, suppression of transmission is removed, input activates the self-organized representation, and activity settles into a learned solution to the problem. This computational model can be used for learning of problems which are not linearly separable, including the negative patterning task (the XOR problem). Experiments in brain slice preparations of the rat somatosensory cortex tested whether the combination of self-organization and associative memory function could be provided by cholinergic suppression selective for feedback versus feedforward synapses. The cholinergic agonist carbachol selectively suppressed synaptic potentials elicited by stimulation of layer I (which contains a high percentage of feedback synapses), while having no effect on synaptic potentials elicited by stimulation of layer IV (with a high percentage of afferent and feedforward synapses).

The role of expression and identity in the face-selective responses of neurons in the temporal visual cortex of the monkey.

Neurophysiological studies have shown that some neurons in the cortex in the superior temporal sulcus and the inferior temporal gyrus of macaque monkeys respond to faces. To determine if facial factors such as expression and identity are encoded independently by face-responsive neurons, 45 neurons were tested on a stimulus set depicting 3 monkeys with 3 expressions each. As tested on a two-way ANOVA, 15 neurons showed response differences to different identities independently of expression, and 9 neurons showed responses to different expressions independently of identity. Three neurons showed significant effects of both factors. Six of the neurons with responses related to expression responded primarily to calm faces, while 2 responded primarily to threat faces. Of a further set of 31 neurons tested on pairs of different expressions, 6 showed strong responses to open-mouth fear or threat expressions, while 2 showed stronger responses to calm faces than threat expressions. Neurons responsive to expression were found primarily in the cortex in the superior temporal sulcus, while neurons responsive to identity were found primarily in the inferior temporal gyrus. The difference in anatomical distribution was statistically significant. This supports the possibility that specific impairments of the recognition of the identity of a face and of its expression in man are due to damage to or disconnection of separate neuronal substrates.

Selective suppression of afferent but not intrinsic fiber synaptic transmission by 2-amino-4-phosphonobutyric acid (AP4) in piriform cortex.

Differences in the glutaminergic modulation of afferent and intrinsic fiber synaptic transmission in piriform (olfactory) cortex were investigated using extracellular and intracellular recording techniques in a transverse slice preparation. 2-Amino-4-phosphonobutyric acid (AP4) strongly suppressed synaptic potentials evoked by afferent fiber stimulation in layer 1a, while having a much weaker effect on synaptic potentials evoked by intrinsic fiber stimulation in layer 1b. Both the racemic mixture and L-(+)-enantiomer of AP4 showed this differential effect. Suppression of afferent fiber synaptic potentials was accompanied by an increase in paired pulse facilitation, suggesting a pre-synaptic mechanism, while intrinsic fiber synaptic potentials showed little change in facilitation. Previous work has shown that cholinergic modulation in piriform cortex appears selective for intrinsic fiber synapses. The present data describes a pre-synaptic glutaminergic modulation complementary to the cholinergic modulation.

Selective suppression of intrinsic but not afferent fiber synaptic transmission by baclofen in the piriform (olfactory) cortex.

The GABAB agonist baclofen has been shown to suppress synaptic transmission in subregions of the hippocampus and in the piriform (olfactory) cortex. Here we report a laminar selectivity of suppression of synaptic potentials in the olfactory cortex. In brain slice preparations, baclofen suppresses extracellularly recorded field potentials at the intrinsic fiber synapses proximal to the superficial pyramidal cell bodies (layer Ib) while leaving the afferent fiber synaptic potentials recorded at the distal dendrites (layer Ia) little affected. This dose-dependent selective suppression of intrinsic fiber synaptic transmission is also correlated with an increase of paired-pulse facilitation. These results suggest that afferent and intrinsic synaptic inputs may be differentially modulated by the activation of GABAB receptors and that this selective suppression is at least partially mediated via a presynaptic mechanism.

Neural activity in the horizontal limb of the diagonal band of broca can be modulated by electrical stimulation of the olfactory bulb and cortex in rats.

Previously published theoretical models of olfactory processing suggest that cholinergic modulatory inputs to the olfactory system should be regulated by neural activity in the olfactory bulb. We tested these predictions using in vivo electrophysiology in rats. We show that the activity of approximately 20% of neurons recorded in the horizontal limb of the diagonal band of Broca (HDB), which is the source of cholinergic projections to the olfactory system, can be modulated by electrical stimulation of either the lateral olfactory tract or the cell body layer of piriform cortex. These data suggest a possible physiological pathway for the proposed regulation of neural activity in the HDB by activity in the olfactory bulb or cortex.

Functional transitions between epileptiform-like activity and associative memory in hippocampal region CA3.

Clinical and experimental observations indicate that the hippocampus is critical in the formation of declarative memories. Interestingly, electrophysiological studies have demonstrated that the region also has a particularly low seizure threshold, where globally synchronous synaptic activity can occur. By using a detailed biophysical model of area CA3, it is shown how septal cholinergic modulation, through three distinct mechanisms, can interact with intrinsic and synaptic conductances to influence population behavior. A dissection of each mechanism demonstrates a variety of population firing activity ranging from fully synchronized behavior to a mixture of repetitive bursting and oscillations in reduced subsets of neurons, ideal for forming accurate associations during a learning and recall task.

The responses of neurons in the cortex in the superior temporal sulcus of the monkey to band-pass spatial frequency filtered faces.

There are neurons in the cortex in the anterior part of the superior temporal sulcus of the macaque monkey with visual responses which would be useful for face recognition (Rolls, 1984; Baylis et al., 1985). To analyze further the information which leads them to respond, their responses were measured to parametrically filtered stimuli. The responses of 48 such single neurons were measured to faces which were digitized and were bandpass spatial frequency filtered. The octave width bands were 2-4, 4-8, 8-16, 16-32, 32-64 and 64-128 cycles per image. It was found that the neurons could respond well to single octaves of the spatial frequencies normally present in faces, that the most effective bands were 4-8, 8-16 and 16-32 cycles per face (cpf), and that the bands 2-4 and 32-64 cpf were partly effective. In investigations of whether the responses of the neurons to an unfiltered face, and to low-pass and high-pass filtered images could be predicted by linear addition of their responses to each of the octave bands shown separately, it was found that the majority of the neurons were non-linear, and responded much less than predicted. It was also shown that this occurred even when the contrast was reduced to 0.25 of that normally present in a face, so that the result was not due just to a ceiling effect of the maximum firing rate. These results help to define parametrically the aspects of the information normally present in a face which are sufficient to produce responses of these neurons to them, and show that linear operations cannot account for information processing in this part of the visual system.