View Article

Abstract

Acetylcholine (ACh), a key neuromodulator, plays a critical role in cognitive function and has garnered significant interest for its involvement in memory processes, particularly in the context of Alzheimer's disease (AD). This review explores the intricate influence of cholinergic modulation on hippocampal activity and memory abilities, shedding light on the role of ACh in AD pathophysiology and memory function. We discuss the atrophy of the cholinergic system in early AD, alterations in ACh receptor function, and the impact of amyloid ? peptide (A?) accumulation on cholinergic dysfunction. Additionally, we examine the modulation of neural pathways within the medial temporal lobe by ACh, focusing on its effects on synaptic plasticity and network dynamics. Furthermore, we explore the complex interplay of ACh in memory processes, highlighting its selective modulation of memory function and the diverse effects of cholinergic enhancement on memory encoding and consolidation. Understanding these complexities is crucial for developing effective therapeutic interventions for memory-related disorders like AD.

Keywords

Acetylcholine, Alzheimer's disease, Memory function, Cholinergic modulation, Hippocampal activity, Synaptic plasticity, Neural pathways.

Introduction

Understanding the Role of Acetylcholine in Alzheimer's disease and Memory Function

Acetylcholine (ACh), identified initially as a neurotransmitter at the neuromuscular junction, has garnered substantial interest for its role as a vital modulator of cognitive functions [1]. Particularly, attention has focused on the cholinergic system due to its implication in dementia, notably Alzheimer’s disease (AD). AD, a progressive neurodegenerative condition primarily affecting mid- to late-age adults, prominently exhibits episodic memory decline from its early stages. Studies have consistently demonstrated cholinergic system atrophy in the basal forebrain of early AD patients and those at high risk of AD development [2]. This atrophy encompasses a decrease in both cholinergic neuron count and choline acetyltransferase levels, crucial for ACh synthesis [3]. Additionally, alterations in muscarinic and nicotinic ACh receptor function are linked to AD pathophysiology [4]. The administration of nicotine, enhancing ACh levels, has shown to improve cognitive functions in elderly individuals prone to memory issues [4, 5]. Conversely, anticholinergic medications, commonly prescribed for gastrointestinal and dizziness disorders, may contribute to dementia, underscoring the cholinergic system's relevance in memory [6]. While the precise pathophysiology of AD remains elusive, extensive human and animal studies suggest a strong correlation between amyloid ? peptide (A?) accumulation and neurofibrillary tangle formation with AD development. Notably, A? accumulation in cholinergic neurons of the basal forebrain correlates with aging and AD progression. A?'s interference with ACh synthesis, release, and receptor signalling further underscores its role in cholinergic dysfunction. Cholinergic dysfunction significantly impacts the hippocampus, a brain region crucial for memory function [7, 8, 9, 10]. Reduced cholinergic projections from the medial septum to the hippocampus, coupled with decreased cholinergic receptor levels and ACh binding, characterize AD patients and mouse models of AD [11, 12, 13] . These findings underscore the critical role of the cholinergic system in hippocampal function and its implication in AD pathology.

Cholinergic Modulation of Cognitive Functions: Insights into Acetylcholine's Neurotransmission and Neuromodulation



       
            Picture1.jpg
       

    Fig. 1. Cholinergic Neurotransmission inside Hippocampal region


Acetylcholine serves as both a neurotransmitter and a neuromodulator in the nervous system, attracting considerable interest for its impact on cognitive functions. Cholinergic neurons, responsible for producing ACh, are distributed throughout the brain, with notable concentrations in regions like the brainstem, basal forebrain, stratum, and medial habenular nucleus. These neurons project to various brain areas, including the thalamus, basal ganglia, tectum, and basal forebrain, influencing diverse neural functions [14, 15, 16, 17, 18]. In the basal forebrain, cholinergic neurons located in regions like the medial septum and diagonal band of Broca provide essential inputs to the hippocampus, crucial for memory formation [19, 20]. Selective lesions of these neurons impair hippocampus-dependent memory function, indicating the significance of septohippocampal cholinergic projections [21]. Similarly, disruptions in the vesicular acetylcholine transporter (VAChT), vital for ACh release, lead to synaptic plasticity impairments in the hippocampus and affect RNA processing in the prefrontal cortex, resulting in memory and attention deficits [22, 23, 24, 25]. Cholinergic receptors comprise two main classes: nicotinic and muscarinic receptors, expressed throughout the central and peripheral nervous systems [26]. Nicotinic receptors are excitatory ion channels, while muscarinic receptors are G protein-coupled receptors. In the hippocampus, nicotinic receptor subtypes like a7 homomeric and a4b2 heteromeric receptors play essential roles in synaptic plasticity and modulate neurotransmitter release. Muscarinic receptors, particularly M1 subtype, regulate neuronal excitability, while M2 and M4 subtypes modulate neurotransmitter release at synaptic terminals [27, 28, 29, 30]. Understanding the distribution and function of these receptors sheds light on the intricate mechanisms underlying cholinergic modulation of neural processes, particularly in cognitive functions.

Modulating neural pathways within the medial temporal lobe through the influence of acetylcholine

Acetylcholine plays a significant role in shaping neuronal circuits, impacting neurogenesis, spine formation, and synapse formation [31]. These lasting alterations necessitate protein synthesis, as evidenced by studies [32]. Furthermore, acetylcholine exerts immediate effects on synaptic plasticity by regulating neuronal spiking activity and neurotransmitter release. This section will delve into the rapid effects of acetylcholine, particularly its correlation with changes in extracellular acetylcholine levels in the medial temporal lobe during the learning process [33].

Inside the Hippocampal region

Research has revealed that cholinergic neurons located in the medial septum play a crucial role in regulating hippocampal circuits. By utilizing optogenetic techniques, scientists have demonstrated that stimulating these cholinergic neurons not only alters the firing patterns of hippocampal neurons but also influences theta-band oscillations within the hippocampus in live subjects [34]. Both experimental and computational studies have shed light on acetylcholine's role in modulating hippocampal pathways involved in memory consolidation and encoding. Acetylcholine selectively inhibits intrinsic pathways, which contribute to memory consolidation circuits, while enhancing afferent projections, which are part of the encoding pathway [35]. Activation of muscarinic acetylcholine receptors in interneurons within the CA3 region suppresses the recurrent pathway, ensuring preferential activation of circuits carrying extrinsic information over intrinsic projections. In the CA1 region of the hippocampus, acetylcholine has been observed to potentiate the Schaffer collateral pathway by activating either a7 or non-a7 nicotinic acetylcholine receptors in pyramidal neurons and GABAergic interneurons. However, there are conflicting findings regarding this effect, with some studies suggesting inhibition of the Schaffer collateral pathway by acetylcholine [36, 37]. This inconsistency may stem from the timing-dependent nature of acetylcholine's impact on synaptic plasticity and the activation of different cholinergic receptor subtypes under varying conditions. Moreover, the frequency of cholinergic neuron stimulation can evoke different responses in hippocampal interneurons, ranging from depolarization to hyperpolarization, mediated by distinct ACh receptor subtypes. In the dentate gyrus, acetylcholine has been found to enhance long-term potentiation through the activation of both nicotinic and muscarinic receptors. Additionally, septal cholinergic projections activate astrocytes to modulate dentate granule cells [38, 39, 40].

Inside the Para hippocampal region

Acetylcholine plays a significant role in modulating neuronal activity within the entorhinal cortex (EC), which serves as a crucial link between the neocortex and hippocampus. Its effects vary depending on the specific circuits within the EC [41]. In the superficial layers (layer I, II, and III), where cortical neurons receiving external signals project, acetylcholine has been observed to increase neuronal spiking and promote synchronized oscillatory activity. These superficial layers are involved in memory encoding and are active during wakefulness. Conversely, the deep layers of the EC (layer V and VI in rodents) receive inputs from the hippocampus and project back to the neocortex for memory consolidation [42, 43]. Deep-layer EC neuron activity peaks during sharp-wave sleep, coinciding with heightened memory consolidation [44]. Studies also indicate that rhythmic activity in these deep layers correlates with hippocampal activity during slow-wave sleep but not wakefulness. Recent unpublished research suggests that acetylcholine activates hippocampal interneurons, which in turn inhibit hippocampal outputs to the deep EC layers. Exploring how cholinergic inputs affect hippocampal area activity poses an intriguing question for further investigation [44].

The intricate interplay of acetylcholine in modulating memory processes

Understanding the intricate effects of medications altering extracellular acetylcholine (ACh) levels or its receptor activity on memory functions is crucial, particularly in the context of Alzheimer's disease treatment. Drugs like donepezil, rivastigmine, and galantamine are commonly prescribed for Alzheimer's patients due to their ability to inhibit acetylcholinesterase, thereby increasing ACh levels. However, the impact of these drugs on memory enhancement can vary significantly among individuals, highlighting the complexity and unpredictability of ACh's role in memory regulation [45]. One fundamental aspect contributing to the complexity of ACh's impact on memory is its selective modulation of memory function. ACh predominantly influences hippocampus-dependent learning, particularly declarative memory such as episodic and semantic memory, while exerting less influence on procedural or implicit memory [46, 47].  Activation of cholinergic receptors is crucial for episodic and spatial memory but less so for procedural memory. Moreover, the manipulation of ACh release through various techniques leads to diverse findings, further complicating the understanding of its role in memory. Cholinergic neurons often release neurotransmitters like GABA and glutamate alongside ACh, complicating the interpretation of experimental results [48, 49,  50]. Studies targeting ACh release selectively or using specific ACh receptor antagonists have provided unique insights compared to studies ablating cholinergic neurons. Another layer of complexity in ACh's modulation of memory lies in its differential effects at various stages of memory processing. While ACh tends to facilitate memory encoding, it may suppress memory consolidation. Memory formation involves two primary stages: encoding, where sensory inputs are relayed from the cortex to the hippocampus, and consolidation, where temporary memories are transferred back to the cortex for long-term storage [51,  52, 53]. ACh seems to play a pivotal role in mediating the transition between these two stages of memory formation. The diversity of ACh receptor subtypes, each exhibiting distinct desensitization characteristics, further adds to the complexity of its effects on memory. Nicotinic ACh receptors, for instance, display various conformations, with a7-containing receptors being particularly prone to rapid desensitization. The kinetics of receptor desensitization can significantly influence the overall effects of ACh on memory function [54,55, 56]. Furthermore, the efficacy of cholinergic enhancement of memory function is closely intertwined with basal cholinergic activity [57]. Individuals with lower baseline cognitive performance may experience more substantial cognitive improvements in response to pharmacological increases in ACh levels compared to those with higher baseline performance [58, 59]. This suggests a nonlinear relationship, resembling an inverted U-shaped curve, between ACh concentration and memory function, where an optimal effect occurs within a specific range of ACh levels. In summary, the intricate interplay of ACh in memory processes involves multiple signaling pathways with opposing effects on memory function [60, 61]. The delicate balance of ACh levels and receptor activity, influenced by factors such as receptor subtype, release modulation, and basal cholinergic activity, ultimately determines its overall impact on memory. A comprehensive understanding of these complexities is indispensable for the development of effective therapeutic interventions for memory-related disorders like Alzheimer's disease [62, 63].


       
            Picture2.jpg
       

    Fig. 2.  Influence of acetylcholine (ACh) on cognitive function is nuanced and intricate

 

  1. ACh's impact on cognitive processes is notably specific, particularly in the realm of hippocampus-dependent memory. It primarily affects spatial memory while leaving procedural memory relatively unaffected.
  2. The method by which ACh is modulated can lead to varying results. For instance, employing optogenetic techniques to manipulate cholinergic neurons is considered more akin to the natural physiological process but lacks the specificity observed with direct antagonism of ACh receptors (AChRs).
  3. ACh exhibits distinct effects on memory encoding and consolidation, with a preference for enhancing pathways involved in encoding information.
  4. Moreover, the responses induced by ACh can vary depending on the specific receptor subtypes it activates. Each subtype has unique desensitization characteristics, leading to differing outcomes in cognitive processes.
  5. The degree to which ACh enhances memory function is contingent upon the baseline cholinergic activity. It tends to have a more pronounced positive effect on individuals with lower baseline ACh levels.

CONCLUSION:

Acetylcholine (ACh) serves as a crucial neuromodulator in cognitive function, particularly in hippocampus-dependent memory. Past studies utilizing various methodologies such as immunohistochemistry, electrophysiology, pharmacology, and behavioral analyses have revealed the multifaceted ways in which ACh influences memory circuits. However, due to the intricate nature of ACh's actions in the brain, research findings have often been met with controversy. A comprehensive understanding of the complexity underlying ACh's actions is essential for unraveling its physiological roles in cognitive functions and for developing improved treatment strategies for age-related dementia. In recent decades, significant advancements have been made in elucidating how ACh modulates memory circuits. Leveraging novel tools now available, investigating ACh's actions at different levels—ranging from cellular mechanisms to network dynamics and behavioral outcomes—will be vital for comprehensively deciphering its complex effects. This holistic approach holds promise for gaining deeper insights into the intricate interplay of ACh in cognitive processes and for guiding the development of more effective therapeutic interventions.

 REFERENCES

  1. Hasselmo ME. The role of acetylcholine in learning and memory. Current opinion in neurobiology. 2006 Dec 1;16(6):710-5.
  2. Rand JB. Acetylcholine. WormBook. 2007:1.
  3. White HL, Cavallito CJ. Choline acetyltransferase: enzyme mechanism and mode of inhibition by a styrylpyridine analogue. Biochimica et Biophysica Acta (BBA)-Enzymology. 1970 Jun 10;206(3):343-58.
  4. Whitehouse PJ, Martino AM, Marcus KA, Zweig RM, Singer HS, Price DL, Kellar KJ. Reductions in acetylcholine and nicotine binding in several degenerative diseases. Archives of neurology. 1988 Jul 1;45(7):722-4.
  5. Wittenberg RE, Wolfman SL, De Biasi M, Dani JA. Nicotinic acetylcholine receptors and nicotine addiction: A brief introduction. Neuropharmacology. 2020 Oct 15;177:108256.
  6. Morley JE. Anticholinergic medications and cognition. Journal of the American Medical Directors Association. 2011 Oct 1;12(8):543.
  7. Imbimbo BP, Lombard J, Pomara N. Pathophysiology of Alzheimer's disease. Neuroimaging clinics. 2005 Nov 1;15(4):727-53.

 

  1. Twohig D, Nielsen HM. ?-synuclein in the pathophysiology of Alzheimer’s disease. Molecular neurodegeneration. 2019 Jun 11;14(1):23.
  2. Morrison AS, Lyketsos C. The pathophysiology of Alzheimer’s disease and directions in treatment. Adv Stud Nurs. 2005;3(8):256-70.
  3. Selkoe DJ. The molecular pathology of Alzheimer's disease. Neuron. 1991 Apr 1;6(4):487-98.
  4. Colgin LL, Krama?r EA, Gall CM, Lynch G. Septal modulation of excitatory transmission in hippocampus. Journal of neurophysiology. 2003 Oct;90(4):2358-66.
  5. Sarter M, Parikh V, Howe WM. Phasic acetylcholine release and the volume transmission hypothesis: time to move on. Nature Reviews Neuroscience. 2009 May;10(5):383-90.
  6. H Ferreira-Vieira T, M Guimaraes I, R Silva F, M Ribeiro F. Alzheimer's disease: targeting the cholinergic system. Current neuropharmacology. 2016 Jan 1;14(1):101-15.
  7. Picciotto MR, Higley MJ, Mineur YS. Acetylcholine as a neuromodulator: cholinergic signaling shapes nervous system function and behavior. Neuron. 2012 Oct 4;76(1):116-29.
  8. Hasselmo ME, Sarter M. Modes and models of forebrain cholinergic neuromodulation of cognition. Neuropsychopharmacology. 2011 Jan;36(1):52-73.
  9. Herlenius E, Lagercrantz H. Neurotransmitters and neuromodulators. The Newborn Brain: Neuroscience and Clinical Applications. Cambridge University Press, Cambridge. 2010:99-119.
  10. und Halbach OV, Dermietzel R. Neurotransmitters and neuromodulators: Handbook of receptors and biological effects. John Wiley & Sons; 2006 Dec 13.
  11. Graybiel AM. Neurotransmitters and neuromodulators in the basal ganglia. Trends in neurosciences. 1990 Jul 1;13(7):244-54.
  12. Cuello AC, Sofroniew MV. The anatomy of the CNS cholinergic neurons. Trends in neurosciences. 1984 Mar 1;7(3):74-8.
  13. Blusztajn JK, Wurtman RJ. Choline and cholinergic neurons. Science. 1983 Aug 12;221(4611):614-20.
  14. Teles-Grilo Ruivo LM, Mellor JR. Cholinergic modulation of hippocampal network function. Frontiers in synaptic neuroscience. 2013 Jul 30;5:2.
  15. Kolisnyk B, Al-Onaizi MA, Hirata PH, Guzman MS, Nikolova S, Barbash S, Soreq H, Bartha R, Prado MA, Prado VF. Forebrain deletion of the vesicular acetylcholine transporter results in deficits in executive function, metabolic, and RNA splicing abnormalities in the prefrontal cortex. Journal of Neuroscience. 2013 Sep 11;33(37):14908-20.
  16. Al-Onaizi M. The Role of Forebrain Cholinergic Signalling in Regulating Hippocampal Function and Neuropathology (Doctoral dissertation, The University of Western Ontario (Canada)).
  17. Zorbaz T, Madrer N, Soreq H. Cholinergic blockade of neuroinflammation: from tissue to RNA regulators. Neuronal signaling. 2022 Apr;6(1):NS20210035.
  18. Moallem S. Abnormal Hippocampal Activation In Freely Behaving Mice Deficient For The Vesicular Acetylcholine Transporter. The University of Western Ontario (Canada); 2015.
  19. Tiwari P, Dwivedi S, Singh MP, Mishra R, Chandy A. Basic and modern concepts on cholinergic receptor: A review. Asian Pacific journal of tropical disease. 2013 Oct 1;3(5):413-20.
  20. Hurst R, Rollema H, Bertrand D. Nicotinic acetylcholine receptors: from basic science to therapeutics. Pharmacology & therapeutics. 2013 Jan 1;137(1):22-54.
  21. Pandya A. Pharmacology of a novel class of allosteric modulators for the alpha4 beta2 sub-type of neuronal nicotinic acetylcholine receptors. University of Alaska Fairbanks; 2009.
  22. Parker RL. Lynx1 Modulation of Nicotinic Acetylcholine Receptors (Doctoral dissertation, California Institute of Technology).
  23. Koller WC, Melamed E. Functional neurochemistry of the basal ganglia.
  24. Lauder JM, Schambra UB. Morphogenetic roles of acetylcholine. Environmental health perspectives. 1999 Feb;107(suppl 1):65-9.
  25. Falls DL, Rosen KM, Corfas G, Lane WS, Fischbach GD. ARIA, a protein that stimulates acetylcholine receptor synthesis, is a member of the neu ligand family. Cell. 1993 Mar 12;72(5):801-13.
  26. Djemil S, Sames AM, Pak DT. ACh transfers: homeostatic plasticity of cholinergic synapses. Cellular and Molecular Neurobiology. 2023 Mar;43(2):697-709.
  27. Mineur YS, Mose TN, Vanopdenbosch L, Etherington IM, Ogbejesi C, Islam A, Pineda CM, Crouse RB, Zhou W, Thompson DC, Bentham MP. Hippocampal acetylcholine modulates stress-related behaviors independent of specific cholinergic inputs. Molecular psychiatry. 2022 Mar;27(3):1829-38
  28. Jiang L, López-Hernández GY, Lederman J, Talmage DA, Role LW. Optogenetic studies of nicotinic contributions to cholinergic signaling in the central nervous system. Reviews in the Neurosciences. 2014 Dec 1;25(6):755-71
  29. Alkondon M, Pereira EF, Eisenberg HM, Albuquerque EX. Choline and selective antagonists identify two subtypes of nicotinic acetylcholine receptors that modulate GABA release from CA1 interneurons in rat hippocampal slices. Journal of Neuroscience. 1999 Apr 1;19(7):2693-705.
  30. Gipson KE, Yeckel MF. Coincident glutamatergic and cholinergic inputs transiently depress glutamate release at rat schaffer collateral synapses. Journal of neurophysiology. 2007 Jun;97(6):4108-19.
  31. Frazier CJ, Strowbridge BW, Papke RL. Nicotinic receptors on local circuit neurons in dentate gyrus: a potential role in regulation of granule cell excitability. Journal of Neurophysiology. 2003 Jun;89(6):3018-28.
  32. Van der Zee EA, Luiten PG. Muscarinic acetylcholine receptors in the hippocampus, neocortex and amygdala: a review of immunocytochemical localization in relation to learning and memory. Progress in neurobiology. 1999 Aug 1;58(5):409-71.
  33. Kekesi O. The effect of chronic and acute inflammatory processes on the electrophysiological properties of the basal forebrain cholinergic system, and the interaction between neuronal and glial cell types.
  34. Haam J, Zhou J, Cui G, Yakel JL. Septal cholinergic neurons gate hippocampal output to entorhinal cortex via oriens lacunosum moleculare interneurons. Proceedings of the National Academy of Sciences. 2018 Feb 20;115(8):E1886-95.
  35. Stiefel KM, Gutkin BS, Sejnowski TJ. The effects of cholinergic neuromodulation on neuronal phase-response curves of modeled cortical neurons. Journal of computational neuroscience. 2009 Apr;26:289-301.
  36. Lukatch HS, Maciver MB. Physiology, pharmacology, and topography of cholinergic neocortical oscillations in vitro. Journal of neurophysiology. 1997 May 1;77(5):2427-45.
  37. Mölle M, Yeshenko O, Marshall L, Sara SJ, Born J. Hippocampal sharp wave-ripples linked to slow oscillations in rat slow-wave sleep. Journal of neurophysiology. 2006 Jul 1.
  38. Marucci G, Buccioni M, Dal Ben D, Lambertucci C, Volpini R, Amenta F. Efficacy of acetylcholinesterase inhibitors in Alzheimer's disease. Neuropharmacology. 2021 Jun 1;190:108352.
  39. Graves L, Pack A, Abel T. Sleep and memory: a molecular perspective. Trends in neurosciences. 2001 Apr 1;24(4):237-43.
  40. Möhler H, Rudolph U. Disinhibition, an emerging pharmacology of learning and memory. F1000Research. 2017;6.
  41. Granger AJ, Mulder N, Saunders A, Sabatini BL. Cotransmission of acetylcholine and GABA. Neuropharmacology. 2016 Jan 1;100:40-6.
  42. Satin LS, Kinard TA. Neurotransmitters and their receptors in the islets of Langerhans of the pancreas: what messages do acetylcholine, glutamate, and GABA transmit?. Endocrine. 1998 Jun;8:213-23.
  43. Li DP, Chen SR, Pan YZ, Levey AI, Pan HL. Role of presynaptic muscarinic and GABAB receptors in spinal glutamate release and cholinergic analgesia in rats. The Journal of physiology. 2002 Sep;543(3):807-18
  44. Douchamps V, Jeewajee A, Blundell P, Burgess N, Lever C. Evidence for encoding versus retrieval scheduling in the hippocampus by theta phase and acetylcholine. Journal of Neuroscience. 2013 May 15;33(20):8689-704.
  45. Puron-Sierra L, Miranda MI. Histaminergic modulation of cholinergic release from the nucleus basalis magnocellularis into insular cortex during taste aversive memory formation. PloS one. 2014 Mar 13;9(3):e91120.
  46. Angela JY, Dayan P. Acetylcholine in cortical inference. Neural Networks. 2002 Jun 1;15(4-6):719-30.
  47. Miwa JM, Freedman R, Lester HA. Neural systems governed by nicotinic acetylcholine receptors: emerging hypotheses. Neuron. 2011 Apr 14;70(1):20-33.
  48. Khanian SS. Effects of Antihistamines on the Function of Human Alpha-7 Nicotinic Acetylcholine Receptors.
  49. Keyser KT, Britto LR, Schoepfer R, Whiting P, Cooper J, Conroy W, Brozozowska-Prechtl A, Karten HJ, Lindstrom J. Three subtypes of alpha-bungarotoxin-sensitive nicotinic acetylcholine receptors are expressed in chick retina. Journal of Neuroscience. 1993 Feb 1;13(2):442-54.
  50. Furey ML, Pietrini P, Haxby JV. Cholinergic enhancement and increased selectivity of perceptual processing during working memory. Science. 2000 Dec 22;290(5500):2315-9.
  51. Sarter MF, Bruno JP. Cognitive functions of cortical ACh: lessons from studies on trans-synaptic modulation of activated efflux. Trends in neurosciences. 1994 Jun 1;17(6):217-21.
  52. Blandina P, Giorgetti M, Bartolini L, Cecchi M, Timmerman H, Leurs R, Pepeu G, Giovannini MG. Inhibition of cortical acetylcholine release and cognitive performance by histamine H3 receptor activation in rats. British journal of pharmacology. 1996 Dec;119(8):1656.
  53. Huang Q, Liao C, Ge F, Ao J, Liu T. Acetylcholine bidirectionally regulates learning and memory. Journal of Neurorestoratology. 2022 Jun 1;10(2):100002.
  54. Hasselmo ME, McGaughy J. High acetylcholine levels set circuit dynamics for attention and encoding and low acetylcholine levels set dynamics for consolidation. Progress in brain research. 2004 Jan 1;145:207-31.
  55. Muir JL. Acetylcholine, aging, and Alzheimer's disease. Pharmacology Biochemistry and Behavior. 1997 Apr 1;56(4):687-96. Muir JL. Acetylcholine, aging, and Alzheimer's disease. Pharmacology Biochemistry and Behavior. 1997 Apr 1;56(4):687-96.
  56. Gil-Bea FJ, García-Alloza M, Domínguez J, Marcos B, Ramírez MJ. Evaluation of cholinergic markers in Alzheimer's disease and in a model of cholinergic deficit. Neuroscience letters. 2005 Feb 25;375(1):37-41

Reference

  1. Hasselmo ME. The role of acetylcholine in learning and memory. Current opinion in neurobiology. 2006 Dec 1;16(6):710-5.
  2. Rand JB. Acetylcholine. WormBook. 2007:1.
  3. White HL, Cavallito CJ. Choline acetyltransferase: enzyme mechanism and mode of inhibition by a styrylpyridine analogue. Biochimica et Biophysica Acta (BBA)-Enzymology. 1970 Jun 10;206(3):343-58.
  4. Whitehouse PJ, Martino AM, Marcus KA, Zweig RM, Singer HS, Price DL, Kellar KJ. Reductions in acetylcholine and nicotine binding in several degenerative diseases. Archives of neurology. 1988 Jul 1;45(7):722-4.
  5. Wittenberg RE, Wolfman SL, De Biasi M, Dani JA. Nicotinic acetylcholine receptors and nicotine addiction: A brief introduction. Neuropharmacology. 2020 Oct 15;177:108256.
  6. Morley JE. Anticholinergic medications and cognition. Journal of the American Medical Directors Association. 2011 Oct 1;12(8):543.
  7. Imbimbo BP, Lombard J, Pomara N. Pathophysiology of Alzheimer's disease. Neuroimaging clinics. 2005 Nov 1;15(4):727-53.

 

  1. Twohig D, Nielsen HM. ?-synuclein in the pathophysiology of Alzheimer’s disease. Molecular neurodegeneration. 2019 Jun 11;14(1):23.
  2. Morrison AS, Lyketsos C. The pathophysiology of Alzheimer’s disease and directions in treatment. Adv Stud Nurs. 2005;3(8):256-70.
  3. Selkoe DJ. The molecular pathology of Alzheimer's disease. Neuron. 1991 Apr 1;6(4):487-98.
  4. Colgin LL, Krama?r EA, Gall CM, Lynch G. Septal modulation of excitatory transmission in hippocampus. Journal of neurophysiology. 2003 Oct;90(4):2358-66.
  5. Sarter M, Parikh V, Howe WM. Phasic acetylcholine release and the volume transmission hypothesis: time to move on. Nature Reviews Neuroscience. 2009 May;10(5):383-90.
  6. H Ferreira-Vieira T, M Guimaraes I, R Silva F, M Ribeiro F. Alzheimer's disease: targeting the cholinergic system. Current neuropharmacology. 2016 Jan 1;14(1):101-15.
  7. Picciotto MR, Higley MJ, Mineur YS. Acetylcholine as a neuromodulator: cholinergic signaling shapes nervous system function and behavior. Neuron. 2012 Oct 4;76(1):116-29.
  8. Hasselmo ME, Sarter M. Modes and models of forebrain cholinergic neuromodulation of cognition. Neuropsychopharmacology. 2011 Jan;36(1):52-73.
  9. Herlenius E, Lagercrantz H. Neurotransmitters and neuromodulators. The Newborn Brain: Neuroscience and Clinical Applications. Cambridge University Press, Cambridge. 2010:99-119.
  10. und Halbach OV, Dermietzel R. Neurotransmitters and neuromodulators: Handbook of receptors and biological effects. John Wiley & Sons; 2006 Dec 13.
  11. Graybiel AM. Neurotransmitters and neuromodulators in the basal ganglia. Trends in neurosciences. 1990 Jul 1;13(7):244-54.
  12. Cuello AC, Sofroniew MV. The anatomy of the CNS cholinergic neurons. Trends in neurosciences. 1984 Mar 1;7(3):74-8.
  13. Blusztajn JK, Wurtman RJ. Choline and cholinergic neurons. Science. 1983 Aug 12;221(4611):614-20.
  14. Teles-Grilo Ruivo LM, Mellor JR. Cholinergic modulation of hippocampal network function. Frontiers in synaptic neuroscience. 2013 Jul 30;5:2.
  15. Kolisnyk B, Al-Onaizi MA, Hirata PH, Guzman MS, Nikolova S, Barbash S, Soreq H, Bartha R, Prado MA, Prado VF. Forebrain deletion of the vesicular acetylcholine transporter results in deficits in executive function, metabolic, and RNA splicing abnormalities in the prefrontal cortex. Journal of Neuroscience. 2013 Sep 11;33(37):14908-20.
  16. Al-Onaizi M. The Role of Forebrain Cholinergic Signalling in Regulating Hippocampal Function and Neuropathology (Doctoral dissertation, The University of Western Ontario (Canada)).
  17. Zorbaz T, Madrer N, Soreq H. Cholinergic blockade of neuroinflammation: from tissue to RNA regulators. Neuronal signaling. 2022 Apr;6(1):NS20210035.
  18. Moallem S. Abnormal Hippocampal Activation In Freely Behaving Mice Deficient For The Vesicular Acetylcholine Transporter. The University of Western Ontario (Canada); 2015.
  19. Tiwari P, Dwivedi S, Singh MP, Mishra R, Chandy A. Basic and modern concepts on cholinergic receptor: A review. Asian Pacific journal of tropical disease. 2013 Oct 1;3(5):413-20.
  20. Hurst R, Rollema H, Bertrand D. Nicotinic acetylcholine receptors: from basic science to therapeutics. Pharmacology & therapeutics. 2013 Jan 1;137(1):22-54.
  21. Pandya A. Pharmacology of a novel class of allosteric modulators for the alpha4 beta2 sub-type of neuronal nicotinic acetylcholine receptors. University of Alaska Fairbanks; 2009.
  22. Parker RL. Lynx1 Modulation of Nicotinic Acetylcholine Receptors (Doctoral dissertation, California Institute of Technology).
  23. Koller WC, Melamed E. Functional neurochemistry of the basal ganglia.
  24. Lauder JM, Schambra UB. Morphogenetic roles of acetylcholine. Environmental health perspectives. 1999 Feb;107(suppl 1):65-9.
  25. Falls DL, Rosen KM, Corfas G, Lane WS, Fischbach GD. ARIA, a protein that stimulates acetylcholine receptor synthesis, is a member of the neu ligand family. Cell. 1993 Mar 12;72(5):801-13.
  26. Djemil S, Sames AM, Pak DT. ACh transfers: homeostatic plasticity of cholinergic synapses. Cellular and Molecular Neurobiology. 2023 Mar;43(2):697-709.
  27. Mineur YS, Mose TN, Vanopdenbosch L, Etherington IM, Ogbejesi C, Islam A, Pineda CM, Crouse RB, Zhou W, Thompson DC, Bentham MP. Hippocampal acetylcholine modulates stress-related behaviors independent of specific cholinergic inputs. Molecular psychiatry. 2022 Mar;27(3):1829-38
  28. Jiang L, López-Hernández GY, Lederman J, Talmage DA, Role LW. Optogenetic studies of nicotinic contributions to cholinergic signaling in the central nervous system. Reviews in the Neurosciences. 2014 Dec 1;25(6):755-71
  29. Alkondon M, Pereira EF, Eisenberg HM, Albuquerque EX. Choline and selective antagonists identify two subtypes of nicotinic acetylcholine receptors that modulate GABA release from CA1 interneurons in rat hippocampal slices. Journal of Neuroscience. 1999 Apr 1;19(7):2693-705.
  30. Gipson KE, Yeckel MF. Coincident glutamatergic and cholinergic inputs transiently depress glutamate release at rat schaffer collateral synapses. Journal of neurophysiology. 2007 Jun;97(6):4108-19.
  31. Frazier CJ, Strowbridge BW, Papke RL. Nicotinic receptors on local circuit neurons in dentate gyrus: a potential role in regulation of granule cell excitability. Journal of Neurophysiology. 2003 Jun;89(6):3018-28.
  32. Van der Zee EA, Luiten PG. Muscarinic acetylcholine receptors in the hippocampus, neocortex and amygdala: a review of immunocytochemical localization in relation to learning and memory. Progress in neurobiology. 1999 Aug 1;58(5):409-71.
  33. Kekesi O. The effect of chronic and acute inflammatory processes on the electrophysiological properties of the basal forebrain cholinergic system, and the interaction between neuronal and glial cell types.
  34. Haam J, Zhou J, Cui G, Yakel JL. Septal cholinergic neurons gate hippocampal output to entorhinal cortex via oriens lacunosum moleculare interneurons. Proceedings of the National Academy of Sciences. 2018 Feb 20;115(8):E1886-95.
  35. Stiefel KM, Gutkin BS, Sejnowski TJ. The effects of cholinergic neuromodulation on neuronal phase-response curves of modeled cortical neurons. Journal of computational neuroscience. 2009 Apr;26:289-301.
  36. Lukatch HS, Maciver MB. Physiology, pharmacology, and topography of cholinergic neocortical oscillations in vitro. Journal of neurophysiology. 1997 May 1;77(5):2427-45.
  37. Mölle M, Yeshenko O, Marshall L, Sara SJ, Born J. Hippocampal sharp wave-ripples linked to slow oscillations in rat slow-wave sleep. Journal of neurophysiology. 2006 Jul 1.
  38. Marucci G, Buccioni M, Dal Ben D, Lambertucci C, Volpini R, Amenta F. Efficacy of acetylcholinesterase inhibitors in Alzheimer's disease. Neuropharmacology. 2021 Jun 1;190:108352.
  39. Graves L, Pack A, Abel T. Sleep and memory: a molecular perspective. Trends in neurosciences. 2001 Apr 1;24(4):237-43.
  40. Möhler H, Rudolph U. Disinhibition, an emerging pharmacology of learning and memory. F1000Research. 2017;6.
  41. Granger AJ, Mulder N, Saunders A, Sabatini BL. Cotransmission of acetylcholine and GABA. Neuropharmacology. 2016 Jan 1;100:40-6.
  42. Satin LS, Kinard TA. Neurotransmitters and their receptors in the islets of Langerhans of the pancreas: what messages do acetylcholine, glutamate, and GABA transmit?. Endocrine. 1998 Jun;8:213-23.
  43. Li DP, Chen SR, Pan YZ, Levey AI, Pan HL. Role of presynaptic muscarinic and GABAB receptors in spinal glutamate release and cholinergic analgesia in rats. The Journal of physiology. 2002 Sep;543(3):807-18
  44. Douchamps V, Jeewajee A, Blundell P, Burgess N, Lever C. Evidence for encoding versus retrieval scheduling in the hippocampus by theta phase and acetylcholine. Journal of Neuroscience. 2013 May 15;33(20):8689-704.
  45. Puron-Sierra L, Miranda MI. Histaminergic modulation of cholinergic release from the nucleus basalis magnocellularis into insular cortex during taste aversive memory formation. PloS one. 2014 Mar 13;9(3):e91120.
  46. Angela JY, Dayan P. Acetylcholine in cortical inference. Neural Networks. 2002 Jun 1;15(4-6):719-30.
  47. Miwa JM, Freedman R, Lester HA. Neural systems governed by nicotinic acetylcholine receptors: emerging hypotheses. Neuron. 2011 Apr 14;70(1):20-33.
  48. Khanian SS. Effects of Antihistamines on the Function of Human Alpha-7 Nicotinic Acetylcholine Receptors.
  49. Keyser KT, Britto LR, Schoepfer R, Whiting P, Cooper J, Conroy W, Brozozowska-Prechtl A, Karten HJ, Lindstrom J. Three subtypes of alpha-bungarotoxin-sensitive nicotinic acetylcholine receptors are expressed in chick retina. Journal of Neuroscience. 1993 Feb 1;13(2):442-54.
  50. Furey ML, Pietrini P, Haxby JV. Cholinergic enhancement and increased selectivity of perceptual processing during working memory. Science. 2000 Dec 22;290(5500):2315-9.
  51. Sarter MF, Bruno JP. Cognitive functions of cortical ACh: lessons from studies on trans-synaptic modulation of activated efflux. Trends in neurosciences. 1994 Jun 1;17(6):217-21.
  52. Blandina P, Giorgetti M, Bartolini L, Cecchi M, Timmerman H, Leurs R, Pepeu G, Giovannini MG. Inhibition of cortical acetylcholine release and cognitive performance by histamine H3 receptor activation in rats. British journal of pharmacology. 1996 Dec;119(8):1656.
  53. Huang Q, Liao C, Ge F, Ao J, Liu T. Acetylcholine bidirectionally regulates learning and memory. Journal of Neurorestoratology. 2022 Jun 1;10(2):100002.
  54. Hasselmo ME, McGaughy J. High acetylcholine levels set circuit dynamics for attention and encoding and low acetylcholine levels set dynamics for consolidation. Progress in brain research. 2004 Jan 1;145:207-31.
  55. Muir JL. Acetylcholine, aging, and Alzheimer's disease. Pharmacology Biochemistry and Behavior. 1997 Apr 1;56(4):687-96. Muir JL. Acetylcholine, aging, and Alzheimer's disease. Pharmacology Biochemistry and Behavior. 1997 Apr 1;56(4):687-96.
  56. Gil-Bea FJ, García-Alloza M, Domínguez J, Marcos B, Ramírez MJ. Evaluation of cholinergic markers in Alzheimer's disease and in a model of cholinergic deficit. Neuroscience letters. 2005 Feb 25;375(1):37-41

Photo
Arnab Roy
Corresponding author

Assistant Professor of Pharmacology, Department of Pharmacy, Faculty of Medical Science and Research, Sai Nath University, Ranchi, Jharkhand 835219, India

Photo
Ankita Singh
Co-author

Associate Professor, Faculty of Medical Science and Research, Sai Nath University, Ranchi, Jharkhand 835219, India.

Photo
Mahesh Kumar Yadav
Co-author

Associate Professor, Faculty of Medical Science and Research, Sai Nath University, Ranchi, Jharkhand 835219, India.

Photo
Indrajeet Kumar Mahto
Co-author

Assistant Professor, Faculty of Medical Science and Research, Sai Nath University, Ranchi, Jharkhand 835219, India.

Photo
Chandan Bauri
Co-author

Student, B. Pharm, Faculty of Medical Science and Research, Sai Nath University, Ranchi, Jharkhand 835219, India.

Photo
Rajan Kumar Mahto
Co-author

Student, B. Pharm, Faculty of Medical Science and Research, Sai Nath University, Ranchi, Jharkhand 835219, India.

Photo
Shiny Kumari
Co-author

Student, B. Pharm, Faculty of Medical Science and Research, Sai Nath University, Ranchi, Jharkhand 835219, India.

Photo
Pratik Kumar
Co-author

Student, B. Pharm, Faculty of Medical Science and Research, Sai Nath University, Ranchi, Jharkhand 835219, India.

Photo
Arti Kumari
Co-author

Student, B. Pharm, Faculty of Medical Science and Research, Sai Nath University, Ranchi, Jharkhand 835219, India.

Photo
Anish Kumar Manoj
Co-author

Student, B. Pharm, Faculty of Medical Science and Research, Sai Nath University, Ranchi, Jharkhand 835219, India.

Photo
Vivek Kumar Gupta
Co-author

Student, B. Pharm, Faculty of Medical Science and Research, Sai Nath University, Ranchi, Jharkhand 835219, India.

Ankita Singh, Mahesh Kumar Yadav, Indrajeet Kumar Mahto, Rajan Kumar Mahto, Chandan Bauri, Shiny Kumari, Pratik Kumar, Arnab Roy, Arti Kumari, Anish Kumar Manoj, Vivek Kumar Gupta, Exploring the Influence of Cholinergic Modulation on Hippocampal Activity and Memory Abilities, Int. J. of Pharm. Sci., 2024, Vol 2, Issue 4, 985-994. https://doi.org/10.5281/zenodo.11060164

More related articles
A Review On: Carica Papaya...
Prathamesh Palase, Trupti Thange, Vishal Gaikwad, ...
Antimicrobial Activity Of Morus Alba Leaf Extract ...
Indranil Chatterjee, Bishan Sarkar, Pritam Ghosh, Suchetan Sarkar...
A Novel Method Development and Validation of Imegl...
Tamil Selvan R , Senthilkumar S K , HARI PRAKASH G, Elakkiya A., ...
Formulation And Evaluation Of Herbal Face Gel Using Cucumber Fruit Extract ...
Savri A. Jadhav, Sadhana Dnyaneshwar Gachande, Dinesh Sanjay Jadhav, Mayur Sakharam Gangurde, ...
Formulation and Evaluation of Anti aging Cream...
Ojasvita Anil Khole, Kamal Bahiram, Vaishnavi godase, Punam Sanap, Pradnya Gaikwad, ...
Related Articles
Formulation and Evaluation of Antifungal and Muscle Relaxant Herbal Bath Bomb Co...
Chetan S. Darne, Monika P. Maske, Pawan A. Gore, Jagdish R. Baheti, ...
A Review On: Carica Papaya...
Prathamesh Palase, Trupti Thange, Vishal Gaikwad, ...
More related articles
A Review On: Carica Papaya...
Prathamesh Palase, Trupti Thange, Vishal Gaikwad, ...
Antimicrobial Activity Of Morus Alba Leaf Extract Against Potent Oral Pathogens ...
Indranil Chatterjee, Bishan Sarkar, Pritam Ghosh, Suchetan Sarkar, ...
A Novel Method Development and Validation of Imeglimin HCl By UV Visible Spectro...
Tamil Selvan R , Senthilkumar S K , HARI PRAKASH G, Elakkiya A., Gayatri M., Gokulraj M., Hajima H.,...
A Review On: Carica Papaya...
Prathamesh Palase, Trupti Thange, Vishal Gaikwad, ...
Antimicrobial Activity Of Morus Alba Leaf Extract Against Potent Oral Pathogens ...
Indranil Chatterjee, Bishan Sarkar, Pritam Ghosh, Suchetan Sarkar, ...
A Novel Method Development and Validation of Imeglimin HCl By UV Visible Spectro...
Tamil Selvan R , Senthilkumar S K , HARI PRAKASH G, Elakkiya A., Gayatri M., Gokulraj M., Hajima H.,...