Persistent firing supported by an intrinsic cellular mechanism in hippocampal CA3 pyramidal cells

Short‐term information retention is crucial for information processing in the brain. It has long been suggested that the hippocampal CA3 region is able to support short‐term information retention through persistent neural firing. Theoretical studies have shown that this persistent firing can be supported by abundant excitatory recurrent connections in CA3. However, it remains unclear whether individual cells can support persistent firing. In this study, using in vitro whole‐cell patch‐clamp recordings in a rat hippocampal slice preparation, we show that hippocampal CA3 pyramidal cells support persistent firing under perfusion of the cholinergic agonist carbachol (10 μm). Furthermore, in contrast to earlier theoretical studies, this persistent firing is independent of ionotropic glutamatergic synaptic transmission and is supported by the calcium‐activated non‐selective cationic current. Because cholinergic receptor activation is crucial for short‐term memory tasks, persistent firing in individual cells may support short‐term information retention in the hippocampal CA3 region.

[1]  Alexander J. Rivest,et al.  Entorhinal Cortex Layer III Input to the Hippocampus Is Crucial for Temporal Association Memory , 2011, Science.

[2]  M. Hasselmo,et al.  Dynamics of learning and recall at excitatory recurrent synapses and cholinergic modulation in rat hippocampal region CA3 , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[3]  C G Gross,et al.  Responses of inferior temporal cortex and hippocampal neurons during delayed matching to sample in monkeys (Macaca fascicularis). , 1994, Behavioral neuroscience.

[4]  D J Willshaw,et al.  An assessment of Marr's theory of the hippocampus as a temporary memory store. , 1990, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

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

[6]  L. Swanson,et al.  Analysis of direct hippocampal cortical field CA1 axonal projections to diencephalon in the rat , 2006, The Journal of comparative neurology.

[7]  R. Klein,et al.  Hepatocyte growth factor, a versatile signal for developing neurons , 1999, Nature Neuroscience.

[8]  Howard Eichenbaum,et al.  Distinct roles for dorsal CA3 and CA1 in memory for sequential nonspatial events. , 2010, Learning & memory.

[9]  Michael E Hasselmo,et al.  Persistent Firing Supported by an Intrinsic Cellular Mechanism in a Component of the Head Direction System , 2009, The Journal of Neuroscience.

[10]  A. Alonso,et al.  Muscarinic modulation of the oscillatory and repetitive firing properties of entorhinal cortex layer II neurons. , 1997, Journal of neurophysiology.

[11]  B. McNaughton,et al.  Hippocampal synaptic enhancement and information storage within a distributed memory system , 1987, Trends in Neurosciences.

[12]  H. Seung,et al.  Robust persistent neural activity in a model integrator with multiple hysteretic dendrites per neuron. , 2003, Cerebral cortex.

[13]  S. D. Berry,et al.  Scopolamine disruption of behavioral and hippocampal responses in appetitive trace classical conditioning , 1999, Behavioural Brain Research.

[14]  D. Amaral.  Emerging principles of intrinsic hippocampal organization , 1993, Current Opinion in Neurobiology.

[15]  June-Seek Choi,et al.  Cholinergic transmission in the dorsal hippocampus modulates trace but not delay fear conditioning , 2010, Neurobiology of Learning and Memory.

[16]  A. E. Butt,et al.  Differential acetylcholine release in the prefrontal cortex and hippocampus during pavlovian trace and delay conditioning , 2011, Neurobiology of Learning and Memory.

[17]  L. Descarries,et al.  Postnatal development of the cholinergic innervation in the dorsal hippocampus of rat: Quantitative light and electron microscopic immunocytochemical study , 2005, The Journal of comparative neurology.

[18]  M. Hasselmo,et al.  Switching between “On” and “Off” states of persistent activity in lateral entorhinal layer III neurons , 2007, Hippocampus.

[19]  Florin Dolcos,et al.  Similarities and Differences in the Neural Correlates of Episodic Memory Retrieval and Working Memory , 2002, NeuroImage.

[20]  S. D. Berry,et al.  Medial septal microinfusion of scopolamine disrupts hippocampal activity and trace jaw movement conditioning. , 2000, Behavioral neuroscience.

[21]  J. Lacaille,et al.  Local circuit interactions between oriens/alveus interneurons and CA1 pyramidal cells in hippocampal slices: electrophysiology and morphology , 1987, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[22]  M. Hasselmo,et al.  Mechanism of Graded Persistent Cellular Activity of Entorhinal Cortex Layer V Neurons , 2006, Neuron.

[23]  T. H. Brown,et al.  Muscarinic receptor activation enables persistent firing in pyramidal neurons from superficial layers of dorsal perirhinal cortex , 2012, Hippocampus.

[24]  P. Pedarzani,et al.  Medium afterhyperpolarization and firing pattern modulation in interneurons of stratum radiatum in the CA3 hippocampal region. , 2001, Journal of neurophysiology.

[25]  Inah Lee,et al.  Differential roles of dorsal hippocampal subregions in spatial working memory with short versus intermediate delay. , 2003, Behavioral neuroscience.

[26]  Shigeyoshi Fujisawa,et al.  Single neurons can induce phase transitions of cortical recurrent networks with multiple internal States. , 2006, Cerebral cortex.

[27]  J. Disterhoft,et al.  Single Neurons in CA1 Hippocampus Encode Trace Interval Duration during Trace Heart Rate (Fear) Conditioning in Rabbit , 2003, The Journal of Neuroscience.

[28]  T. Freund,et al.  Precision and Variability in Postsynaptic Target Selection of Inhibitory Cells in the Hippocampal CA3 Region , 1993, The European journal of neuroscience.

[29]  M. Hasselmo,et al.  Graded persistent activity in entorhinal cortex neurons , 2002, Nature.

[30]  B. McNaughton,et al.  Reactivation of hippocampal ensemble memories during sleep. , 1994, Science.

[31]  John D E Gabrieli,et al.  Performance-Related Sustained and Anticipatory Activity in Human Medial Temporal Lobe during Delayed Match-to-Sample , 2009, The Journal of Neuroscience.

[32]  R. F. Thompson,et al.  Hippocampus and trace conditioning of the rabbit's classically conditioned nictitating membrane response. , 1986, Behavioral neuroscience.

[33]  H. Niki,et al.  Hippocampal unit activity and delayed response in the monkey , 1985, Brain Research.

[34]  David S. Olton,et al.  Spatial memory following damage to hippocampal CA3 pyramidal cells with kainic acid: impairment and recovery with preoperative training , 1981, Brain Research.

[35]  R. Bartus,et al.  Short-term memory in the rhesus monkey: Disruption from the anti-cholinergic scopolamine , 1976, Pharmacology Biochemistry and Behavior.

[36]  Michael E Hasselmo,et al.  Mglur-dependent Persistent Firing in Entorhinal Cortex Layer Iii Neurons , 2022 .

[37]  Paul E. Gilbert,et al.  A Behavioral Assessment of Hippocampal Function Based on a Subregional Analysis , 2004, Reviews in the neurosciences.

[38]  W. Regehr,et al.  Cholinergic Modulation of Excitatory Synaptic Transmission in the CA3 Area of the Hippocampus , 2001, The Journal of Neuroscience.

[39]  Peter Jonas,et al.  Patch-clamp recording from mossy fiber terminals in hippocampal slices , 2006, Nature Protocols.

[40]  Howard V. Wheal,et al.  In vivo and in vitro studies on putative interneurones in the rat hippocampus: Possible mediators of feed-forward inhibition , 1984, Brain Research.

[41]  M. Hasselmo,et al.  Scopolamine Reduces Persistent Activity Related to Long-Term Encoding in the Parahippocampal Gyrus during Delayed Matching in Humans , 2005, The Journal of Neuroscience.

[42]  U. Stäubli,et al.  Short‐term reverberant memory model of hippocampal field CA3 , 1997, Hippocampus.

[43]  Phillip J. Best,et al.  Reliability of the relationship between hippocampal unit activity and sensory-behavioral events in the rat , 1982, Experimental Neurology.

[44]  D Marr,et al.  Simple memory: a theory for archicortex. , 1971, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[45]  M. Sarter,et al.  Article Prefrontal Acetylcholine Release Controls Cue Detection on Multiple Timescales , 2022 .

[46]  Philippe Séguéla,et al.  Development of cholinergic modulation and graded persistent activity in layer v of medial entorhinal cortex. , 2007, Journal of neurophysiology.

[47]  T. Robbins,et al.  Effects of scopolamine on delayed-matching-to-sample and paired associates tests of visual memory and learning in human subjects: comparison with diazepam and implications for dementia , 1997, Psychopharmacology.

[48]  S. Dunnett,et al.  Cholinergic blockade in prefrontal cortex and hippocampus disrupts short-term memory in rats. , 1990, NeuroReport.

[49]  J. Delgado-García,et al.  Cholinergic septo-hippocampal innervation is required for trace eyeblink classical conditioning. , 2005, Learning & memory.

[50]  Alcino J. Silva,et al.  Selective cognitive dysfunction in acetylcholine M1 muscarinic receptor mutant mice , 2003, Nature Neuroscience.

[51]  D. Penetar,et al.  Effects of cholinergic drugs on delayed match-to-sample performance of rhesus monkeys , 1983, Pharmacology Biochemistry and Behavior.

[52]  Menno P. Witter,et al.  Place Cells and Place Recognition Maintained by Direct Entorhinal-Hippocampal Circuitry , 2002, Science.

[53]  R. Sutherland,et al.  A behavioural analysis of spatial localization following electrolytic, kainate- or colchicine-induced damage to the hippocampal formation in the rat , 1983, Behavioural Brain Research.

[54]  Jae-Wook Ryou,et al.  Lesions of the Entorhinal Cortex Impair Acquisition of Hippocampal-Dependent Trace Conditioning , 2001, Neurobiology of Learning and Memory.

[55]  N. Spruston,et al.  Slow integration leads to persistent action potential firing in distal axons of coupled interneurons , 2010, Nature Neuroscience.

[56]  U. Zabel,et al.  FRET-based sensors for the human M1-, M3-, and M5-acetylcholine receptors. , 2011, Bioorganic & medicinal chemistry.

[57]  J. Lacaille,et al.  Interneuron Diversity series: Hippocampal interneuron classifications – making things as simple as possible, not simpler , 2003, Trends in Neurosciences.

[58]  J F Disterhoft,et al.  Aging and learning-specific changes in single-neuron activity in CA1 hippocampus during rabbit trace eyeblink conditioning. , 2001, Journal of neurophysiology.

[59]  J. Disterhoft,et al.  Cholinergic facilitation of trace eyeblink conditioning in aging rabbits. , 1999, Life sciences.

[60]  D. Olton,et al.  Basal forebrain cholinergic system: a functional analysis. , 1991, Advances in experimental medicine and biology.

[61]  John F. Disterhoft,et al.  Learning, aging and intrinsic neuronal plasticity , 2006, Trends in Neurosciences.

[62]  D. Olton,et al.  Spatial correlates of hippocampal unit activity , 1978, Experimental Neurology.

[63]  B L McNaughton,et al.  Path Integration and Cognitive Mapping in a Continuous Attractor Neural Network Model , 1997, The Journal of Neuroscience.

[64]  J. N. P. Rawlins,et al.  The effects of delaying reward on choice preference in rats with hippocampal or selective septal lesions , 1985, Behavioural Brain Research.

[65]  P. Somogyi,et al.  Defined types of cortical interneurone structure space and spike timing in the hippocampus , 2005, The Journal of physiology.

[66]  M. Moser,et al.  Impaired retention of spatial memory after transection of longitudinally oriented axons of hippocampal CA3 pyramidal cells , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[67]  Theo G. M. van Erp,et al.  Hippocampal activations during encoding and retrieval in a verbal working memory paradigm , 2005, NeuroImage.

[68]  A. Jochems,et al.  Cholinergic modulation of the CAN current may adjust neural dynamics for active memory maintenance, spatial navigation and time-compressed replay , 2012, Front. Neural Circuits.

[69]  S. D. Berry,et al.  Inactivation of the anterior cingulate cortex impairs extinction of rabbit jaw movement conditioning and prevents extinction-related inhibition of hippocampal activity. , 2004, Learning & memory.

[70]  M. Hasselmo,et al.  Cholinergic suppression of glutamatergic synaptic transmission in hippocampal region CA3 exhibits laminar selectivity: Implication for hippocampal network dynamics , 2007, Neuroscience.

[71]  D. Tank,et al.  Persistent neural activity: prevalence and mechanisms , 2004, Current Opinion in Neurobiology.

[72]  The effects of physostigmine and scopolamine on memory for food caches in the black-capped chickadee , 1994, Pharmacology Biochemistry and Behavior.

[73]  Bruce L. McNaughton,et al.  Path integration and the neural basis of the 'cognitive map' , 2006, Nature Reviews Neuroscience.

[74]  J. Disterhoft,et al.  Activity of hippocampal pyramidal neurons during trace eyeblink conditioning , 1998, Hippocampus.

[75]  J. O'Keefe,et al.  The hippocampus as a spatial map. Preliminary evidence from unit activity in the freely-moving rat. , 1971, Brain research.

[76]  P. Schwartzkroin,et al.  Physiological and morphological identification of a nonpyramidal hippocampal cell type , 1978, Brain Research.

[77]  R. Miles,et al.  Excitatory synaptic interactions between CA3 neurones in the guinea‐pig hippocampus. , 1986, The Journal of physiology.

[78]  K. Mitchell,et al.  Acetylcholine and choline amperometric enzyme sensors characterized in vitro and in vivo. , 2004, Analytical chemistry.

[79]  B. Sakmann,et al.  Ca2+ buffering and action potential-evoked Ca2+ signaling in dendrites of pyramidal neurons. , 1996, Biophysical journal.

[80]  R. Muller,et al.  Muscarinic Blockade Slows and Degrades the Location-Specific Firing of Hippocampal Pyramidal Cells , 2003, The Journal of Neuroscience.

[81]  N. Spruston,et al.  Interneurons in the stratum lucidum of the rat hippocampus: An anatomical and electrophysiological characterization , 1997, The Journal of comparative neurology.

[82]  M. D’Esposito,et al.  Medial Temporal Lobe Activity Associated with Active Maintenance of Novel Information , 2001, Neuron.

[83]  D. Amaral,et al.  Neurons, numbers and the hippocampal network. , 1990, Progress in brain research.

[84]  E. Rolls,et al.  Computational analysis of the role of the hippocampus in memory , 1994, Hippocampus.

[85]  C. Valenzuela,et al.  Block of hippocampal CAN channels by flufenamate , 2000, Brain Research.

[86]  L. Jiménez‐Díaz,et al.  TRP channels and neural persistent activity. , 2011, Advances in experimental medicine and biology.

[87]  Terrence R Stanford,et al.  Categorization in the monkey hippocampus: a possible mechanism for encoding information into memory. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[88]  T. Kaneko,et al.  Disruption of trace conditioning of the nictitating membrane response in rabbits by central cholinergic blockade , 1997, Psychopharmacology.

[89]  A. Alonso,et al.  TRPC channels underlie cholinergic plateau potentials and persistent activity in entorhinal cortex , 2011, Hippocampus.