Combined Blockade of Cholinergic Receptors Shifts the Brain from Stimulus Encoding to Memory Consolidation

High central nervous system levels of acetylcholine (ACh) are commonly regarded as crucial for learning and memory, and a decline in cholinergic neurotransmission is associated with Alzheimer's dementia. However, recent findings revealed exceptions to this rule: The low ACh tone characterizing slowwave sleep (SWS) has proven necessary for consolidation of hippocampus-dependent declarative memories during this sleep stage. Such observations, together with recent models of a hippocampal-neocortical dialogue underlying systems memory consolidation, suggest that high levels of ACh support memory encoding, whereas low levels facilitate consolidation. We tested this hypothesis in human subjects by blocking cholinergic neurotransmission during wakefulness, starting 30 min after learning. Subjects received the muscarinic antagonist scopolamine (4 g/kg bodyweight intravenously) and the nicotinic antagonist mecamylamine (5 mg orally). Compared to placebo, combined muscarinic and nicotinic receptor blockade significantly improved consolidation of declarative memories tested 10 hr later, but simultaneously impaired acquisition of similar material. Consolidation of procedural memories, which are not dependent on hippocampal functioning, was unaffected. Neither scopolamine nor mecamylamine alone enhanced declarative memory consolidation. Our findings support the notion that ACh acts as a switch between modes of acquisition and consolidation. We propose that the natural shift in central nervous system cholinergic tone from high levels during wakefulness to minimal levels during SWS optimizes declarative memory consolidation during a period with no need for new memory encoding.

[1]  B. Adinoff,et al.  The Role of Acetylcholine in Cocaine Addiction , 2008, Neuropsychopharmacology.

[2]  H. Soreq,et al.  Transgenic inactivation of acetylcholinesterase impairs homeostasis in mouse hippocampal granule cells , 2008, Hippocampus.

[3]  J. Born,et al.  Maintaining memories by reactivation , 2007, Current Opinion in Neurobiology.

[4]  J. Born,et al.  The contribution of sleep to hippocampus-dependent memory consolidation , 2007, Trends in Cognitive Sciences.

[5]  Lisa M. Giocomo,et al.  Neuromodulation by Glutamate and Acetylcholine can Change Circuit Dynamics by Regulating the Relative Influence of Afferent Input and Excitatory Feedback , 2007, Molecular Neurobiology.

[6]  J. Born,et al.  The impact of post-learning sleep vs. wakefulness on recognition memory for faces with different facial expressions , 2007, Neurobiology of Learning and Memory.

[7]  I. Izquierdo,et al.  Participation of hippocampal nicotinic receptors in acquisition, consolidation and retrieval of memory for one trial inhibitory avoidance in rats , 2004, Neuroscience.

[8]  J. Born,et al.  Transcranial Direct Current Stimulation during Sleep Improves Declarative Memory , 2004, The Journal of Neuroscience.

[9]  J. Born,et al.  Declarative memory consolidation: mechanisms acting during human sleep. , 2004, Learning & memory.

[10]  C. Degueldre,et al.  Are Spatial Memories Strengthened in the Human Hippocampus during Slow Wave Sleep? , 2004, Neuron.

[11]  R. Stickgold,et al.  Sleep-Dependent Learning and Memory Consolidation , 2004, Neuron.

[12]  J. Born,et al.  Learning increases human electroencephalographic coherence during subsequent slow sleep oscillations. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[13]  J. Born,et al.  Low acetylcholine during slow-wave sleep is critical for declarative memory consolidation , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[14]  Michael E Hasselmo,et al.  Blockade of central cholinergic receptors impairs new learning and increases proactive interference in a word paired-associate memory task. , 2004, Behavioral neuroscience.

[15]  J. Born,et al.  Sleep inspires insight , 2004, Nature.

[16]  Y. Dudai.  The neurobiology of consolidations, or, how stable is the engram? , 2004, Annual review of psychology.

[17]  J. Vanderploeg,et al.  Pharmacokinetics and Oral Bioavailability of Scopolamine in Normal Subjects , 1989, Pharmaceutical Research.

[18]  R. Petersen,et al.  Scopolamine induced learning failures in man , 1977, Psychopharmacology.

[19]  S. Mewaldt,et al.  Effects of diazepam and scopolamine on storage, retrieval and organizational processes in memory , 1975, Psychopharmacologia.

[20]  M. Hasselmo,et al.  High acetylcholine levels set circuit dynamics for attention and encoding and low acetylcholine levels set dynamics for consolidation. , 2004, Progress in brain research.

[21]  R. Kesner,et al.  Cholinergic modulation of the hippocampus during encoding and retrieval , 2003, Neurobiology of Learning and Memory.

[22]  F. Bermúdez-Rattoni,et al.  Role of cholinergic system on the construction of memories: Taste memory encoding , 2003, Neurobiology of Learning and Memory.

[23]  J. D. McGaugh,et al.  Muscarinic cholinergic influences in memory consolidation , 2003, Neurobiology of Learning and Memory.

[24]  R. Stickgold,et al.  Dissociable stages of human memory consolidation and reconsolidation , 2003, Nature.

[25]  T. Maviel,et al.  Role of central cholinergic receptor sub-types in spatial working memory: a five-arm maze task in mice provides evidence for a functional role of nicotinic receptors in mediating trace access processes , 2003, Neuroscience.

[26]  H. Feldman,et al.  Treatment of Alzheimer's disease; current status and new perspectives , 2003, The Lancet Neurology.

[27]  Michael E Hasselmo,et al.  Scopolamine impairs human recognition memory: data and modeling. , 2003, Behavioral neuroscience.

[28]  P. E. Gold,et al.  Switching Memory Systems during Learning: Changes in Patterns of Brain Acetylcholine Release in the Hippocampus and Striatum in Rats , 2003, The Journal of Neuroscience.

[29]  Albert K. Lee,et al.  Memory of Sequential Experience in the Hippocampus during Slow Wave Sleep , 2002, Neuron.

[30]  J. Hobson,et al.  The Neurobiology of Sleep: Genetics, cellular physiology and subcortical networks , 2002, Nature Reviews Neuroscience.

[31]  R. Schwarting,et al.  Open Field Habituation Learning Is Improved by Nicotine and Attenuated by Mecamylamine Administered Posttrial into the Nucleus Accumbens , 2002, Neurobiology of Learning and Memory.

[32]  David R. Vago,et al.  Intrahippocampal Scopolamine Impairs Both Acquisition and Consolidation of Contextual Fear Conditioning , 2001, Neurobiology of Learning and Memory.

[33]  T. George,et al.  Mecamylamine: new therapeutic uses and toxicity/risk profile. , 2001, Clinical therapeutics.

[34]  D. Rasmusson.  The role of acetylcholine in cortical synaptic plasticity , 2000, Behavioural Brain Research.

[35]  J. D. McGaugh,et al.  Behavioural pharmacology and its contribution to the molecular basis of memory consolidation. , 2000, Behavioural pharmacology.

[36]  R. Bartus,et al.  On Neurodegenerative Diseases, Models, and Treatment Strategies: Lessons Learned and Lessons Forgotten a Generation Following the Cholinergic Hypothesis , 2000, Experimental Neurology.

[37]  M. Hasselmo,et al.  Muscarinic cholinergic neuromodulation reduces proactive interference between stored odor memories during associative learning in rats. , 2000, Behavioral neuroscience.

[38]  R. Schwarting,et al.  Injections of Tacrine and Scopolamine into the Nucleus Accumbens: Opposing Effects of Immediate vs Delayed Posttrial Treatment on Memory of an Open Field , 2000, Neurobiology of Learning and Memory.

[39]  J. D. McGaugh.  Memory--a century of consolidation. , 2000, Science.

[40]  Michael S Fanselow,et al.  Scopolamine and Pavlovian Fear Conditioning in Rats: Dose-Effect Analysis , 1999, Neuropsychopharmacology.

[41]  M. Hasselmo.  Neuromodulation: acetylcholine and memory consolidation , 1999, Trends in Cognitive Sciences.

[42]  Trey Sunderland,et al.  Combined Nicotinic and Muscarinic Blockade in Elderly Normal Volunteers: Cognitive, Behavioral, and Physiologic Responses , 1998, Neuropsychopharmacology.

[43]  Michael E. Ragozzino,et al.  Modulation of Hippocampal Acetylcholine Release and Spontaneous Alternation Scores by Intrahippocampal Glucose Injections , 1998, The Journal of Neuroscience.

[44]  M. Hasselmo,et al.  Free recall and recognition in a network model of the hippocampus: simulating effects of scopolamine on human memory function , 1997, Behavioural Brain Research.

[45]  R. Prado-Alcalá,et al.  Selective M1 muscarinic receptor antagonists disrupt memory consolidation of inhibitory avoidance in rats , 1997, Neuroscience Letters.

[46]  J. Born,et al.  Effects of Early and Late Nocturnal Sleep on Declarative and Procedural Memory , 1997, Journal of Cognitive Neuroscience.

[47]  T. Robbins,et al.  Central cholinergic systems and cognition. , 1997, Annual review of psychology.

[48]  G Buzsáki,et al.  The hippocampo-neocortical dialogue. , 1996, Cerebral cortex.

[49]  J. W. Rudy,et al.  Scopolamine Administered before and after Training Impairs both Contextual and Auditory-Cue Fear Conditioning , 1996, Neurobiology of Learning and Memory.

[50]  A. Blokland.  Acetylcholine: a neurotransmitter for learning and memory? , 1995, Brain Research Reviews.

[51]  James L. McClelland,et al.  Why there are complementary learning systems in the hippocampus and neocortex: insights from the successes and failures of connectionist models of learning and memory. , 1995, Psychological review.

[52]  M. Hasselmo,et al.  Modulation of the input/output function of rat piriform cortex pyramidal cells. , 1994, Journal of neurophysiology.

[53]  L. Angelucci,et al.  Effects of concomitant nicotinic and muscarinic blockade on spatial memory disturbance in rats are purely additive: Evidence from the morris water task , 1994, Physiology & Behavior.

[54]  J. Corwin,et al.  Age-Related Effects of the Nicotinic Antagonist Mecamylamine on Cognition and Behavior , 1994, Neuropsychopharmacology.

[55]  F. Bymaster,et al.  Comparative behavioral and neurochemical activities of cholinergic antagonists in rats. , 1993, The Journal of pharmacology and experimental therapeutics.

[56]  P. Boer,et al.  Raised glucose levels enhance scopolamine-induced acetylcholine overflow from the hippocampus: an in vivo microdialysis study in the rat , 1992, Behavioural Brain Research.

[57]  T. A. Pitler,et al.  Cholinergic excitation of GABAergic interneurons in the rat hippocampal slice. , 1992, The Journal of physiology.

[58]  G. Buzsáki.  Two-stage model of memory trace formation: A role for “noisy” brain states , 1989, Neuroscience.

[59]  L. Butcher,et al.  Effects of combined muscarinic and nicotinic blockade on choice accuracy in the radial-arm maze. , 1989, Behavioral and neural biology.

[60]  D. K. Rush,et al.  Scopolamine amnesia of passive avoidance: a deficit of information acquisition. , 1988, Behavioral and neural biology.

[61]  D. Ingram,et al.  Scopolamine in rats impairs acquisition but not retention in a 14-unit T-maze , 1988, Pharmacology Biochemistry and Behavior.

[62]  T. Teyler.  Long-term potentiation and memory. , 1987, International journal of neurology.

[63]  D. Collerton,et al.  Cholinergic function and intellectual decline in Alzheimer's disease , 1986, Neuroscience.

[64]  A Cherkin,et al.  Scopolamine effects on memory retention in mice: a model of dementia? , 1986, Behavioral and neural biology.

[65]  R. Bartus,et al.  The cholinergic hypothesis of geriatric memory dysfunction. , 1982, Science.

[66]  S. Mewaldt,et al.  The effects and interactions of scopolamine, physostigmine and methamphetamine on human memory , 1979, Pharmacology Biochemistry and Behavior.

[67]  S. D. Glick,et al.  Differential effects of scopolamine and mecamylamine on passive avoidance behavior. , 1972, Life sciences. Pt. 1: Physiology and pharmacology.

[68]  D. Safer,et al.  The central effects of scopolamine in man. , 1971, Biological psychiatry.