ACh may set the dynamics of cortical function to those ap-propriate for learning new information. In models of the pu-tative associative memory function of piriform cortex, se-lective suppression of intrinsic but not afferent fiber synaptic transmission by ACh prevents recall of previous input from interfering with the learning of new input (Hasselmo, 1993). Selective cholinergic suppression may play a similar role in the hippocampal formation, where Schaffer collateral syn-apses in stratum radiatum (s. rad) may store associations between activity in region CA3 and the entorhinal cortex input to region CA1 terminating in stratum lacunosum-mo-leculare (s. l-m). A computational model of region CA1 pre-dicts that for effective associative memory function of the Schaffer collaterals, cholinergic suppression of synaptic transmission should be stronger in s. rad than in s. l-m. In the hippocampal slice preparation, we tested the effect of the cholinergic agonist carbachol (0.01-500 PM) on syn-aptic transmission in s. rad and s. l-m. Stimulating and re-cording electrodes were simultaneously placed in both lay-ers, allowing analysis of the effect of carbachol on synaptic potentials in both layers during the same perfusion in each slice. Carbachol produced a significantly stronger suppres-sion of stimulus-evoked EPSPs in s. rad than in s. I-m at all concentrations greater than 1 FM. At 100 PM, EPSP initial slopes were suppressed by 89.1 * 3.0 % in s. rad, but only by 40.1 + 4.1 % in s. l-m. The muscarinic antagonist atropine (1 PM) blocked cholinergic suppression in both layers. These data support the hypothesis that synaptic modification of the Schaffer collaterals may store associations between ac-tivity in region CA3 and the afferent input to region CA1 from the entorhinal cortex. In simulations, feedback regulation of cholinergic modulation based on activity in region CA1 sets the appropriate dynamics of learning for novel associations, and recall for familiar associations.

This research focuses on linking episodic memory function to the cellular physiology of hippocampal neurons, with a particular emphasis on modulatory effects at cholinergic and gg-aminobutyric acid B receptors. Drugs which block acetylcholine receptors (e.g., scopolamine) have been shown to impair encoding of new information in humans, nonhuman primates, and rodents. Extensive data have been gathered about the cellular effects of acetylcholine in the hippocampus. In this research, models of individual hippocampal subregions have been utilized to understand the significance of particular features of modulation, and these hippocampal subregions have been combined in a network simulation which can replicate the selective encoding impairment produced by scopolamine in human subjects. r 1997 Wiley-Liss, Inc.

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 interfere...

In a slice preparation of rat visual cortex, we discovered that paired-pulse stimulation (PPS) elicits a form of homosynaptic long-term depression (LTD) in the superficial layers when carbachol (CCh) or norepinephrine (NE) is applied concurrently. PPS by itself, or CCh and NE in the absence of synaptic stimulation, produced no lasting change. The LTD induced by PPS in the presence of NE or CCh is of comparable magnitude with that obtained with prolonged low-frequency stimulation (LFS) but requires far fewer stimulation pulses (40 vs 900). The cholinergic facilitation of LTD was blocked by atropine and pirenzepine, suggesting involvement of M 1 receptors. The noradrenergic facilitation of LTD was blocked by urapidil and was It is well established that synapses in sensory neocortex can be modified by experience. For example, brief deprivation of normal vision during early postnatal development can lead to a depression

In pyramidal neurons from the CA1 region of the rat hippocampus, Na �-dependent action potentials backpropagate over the dendrites in an activity-dependent manner. Consequently, later spikes in a train have smaller amplitudes when recorded in the apical arbors. We studied the effect of the cholinergic agonist carbachol (CCh) on this pattern of activity when spikes were evoked synaptically or antidromically in the transverse slice preparation. Concentrations as low as 1 �M were effective in reversing the modulation, making the amplitude of all spikes in a train equal and independent of the frequency of spike firing. CCh did not change the propagation of the first spike in a train. These effects of CCh were blocked by 1 �M atropine, showing that only muscarinic receptors were involved. The effects of CCh on the pattern of spike propagation were observed in the proximal and middle dendrites, but recordings in the distal

Experimental data and computational models suggest that blockade of muscarinic cholinergic receptors impairs paired-associate learning and increases proactive interference (E. DeRosa & M. E. Hasselmo, 2000; M. E. Hasselmo & J. M. Bower, 1993). The results presented here provide evidence in humans supporting these hypotheses. Young healthy subjects first learned baseline word pairs (A–B) and, after a delay, learned additional overlapping (A–C) and nonoverlapping (D–E) word pairs. As predicted, when compared with subjects who received the active placebo glycopyrrolate (4 �g/kg) and subjects who were not injected, those who received scopolamine (8 �g/kg) showed (a) overall impairment in new word paired-associate learning, but no impairment in cued recall of previously learned associates; and (b) greater impairment in learning overlapping (A–C) compared with nonoverlapping (D–E) paired associates. Acetylcholine may play an important role in the encoding of new information. Numerous studies demonstrate that blockade of muscarinic acetylcholine receptors by systemic administration of the drug scopolamine interferes with the encoding of new verbal

Computational modeling assists in analyzing the specific functional role of the cellular e#ects of acetylcholine within cortical structures. In particular, acetylcholine may regulate the dynamics of encoding and retrieval of information by regulating the magnitude of synaptic transmission at excitatory recurrent connections. Many abstract models of associative memory function ignore the influence of changes in synaptic strength during the storage process and apply the e#ect of these changes only during a socalled recall-phase. E#orts to ensure stable activity with more realistic, continuous updating of the synaptic strength during the storage process have shown that the memory capacity of a realistic cortical network can be greatly enhanced if cholinergic modulation blocks transmission at synaptic connections of the association fibers during the learning process. We here present experimental data from an olfactory cortex brain slice preparation showing that previously potentiated fibers show significantly greater suppression (presynaptic inhibition) by the cholinergic agonist carbachol than unpotentiated fibers. We conclude that low suppression of non-potentiated fibers during the learning process ensures the formation of self-organized representations in the neural network while the higher suppression of previously potentiated fibers minimizes interference between overlapping patterns. We show in a computational model of olfactory cortex, that, together, these two phenomena reduce the overlap between patterns that are stored within the same neural network structure. These results further demonstrate the contribution of acetylcholine to mechanisms of cortical plasticity. The results are consistent with the extensive evidence supporting a role for acetylcholine in encodi...

As indicated by the profound cognitive impairments caused by cholinergic receptor antagonists, cholinergic neurotransmission has a vital role in cognitive function, specifically attention and memory encoding. Abnormally regulated cholinergic neurotransmission has been hypothesized to contribute to the cognitive symptoms of neuropsychiatric disorders. Loss of cholinergic neurons enhances the severity of the symptoms of dementia. Cholinergic receptor agonists and acetylcholinesterase inhibitors have been investigated for the treatment of cognitive dysfunction. Evidence from experiments using new techniques for measuring rapid changes in cholinergic neurotransmission provides a novel perspective on the cholinergic regulation of cognitive processes. This evidence indicates that changes in cholinergic modulation on a timescale of seconds is triggered by sensory input cues and serves to facilitate cue detection and attentional performance. Furthermore, the evidence indicates cholinergic induction of evoked intrinsic, persistent spiking mechanisms for active maintenance of sensory input, and planned responses. Models have been developed to describe the neuronal mechanisms underlying the transient modulation of cortical target circuits by cholinergic activity. These models postulate specific locations and roles of nicotinic and muscarinic acetylcholine receptors and that cholinergic neurotransmission is controlled in part by (cortical) target circuits. The available evidence and these models point to new principles governing the development of the

Nerve growth factor (NGF) is produced in the hippocampus throughout life and is retrogradely trafficked to septal cholinergic neurons, providing a potential mechanism for modulating cholinergic inputs and, thereby, hippocampal plasticity. To explore NGF modulation of hippocampal plasticity and function, NGF levels were augmented or blocked in intact adult rats, and subsequent in vivo effects on cholinergic neurons, hippocampal long-term potentiation (LTP), and learning were examined. NGF augmentation significantly enhanced cholinergic neuronal markers and facilitated induction of hippocampal LTP. Blockade of endogenous NGF significantly reduced hippocampal LTP and impaired retention of spatial memory. These findings reveal an essential role for NGF in regulating biological mechanisms related to plasticity and memory in the intact adult brain.

Abstract not found