Retrieval associated cholinergic activity and its inhibition by memory updating

doi:10.1016/0024-3205(94)00852-3

Life Sciences

Volume 54, Issue 17, 1994, Pages 1251-1257

https://doi.org/10.1016/0024-3205(94)00852-3 Get rights and content

Abstract

Both hippocampal cholinergic and glutamatergic systems are believed to be engaged in learning and memory. By measuring behavior and ex vivo second messenger inositol phosphate (IP) accumulation, we investigated biochemical responses of cholinergic receptors to retrieval and acquisition processes in rats trained in a spatial task. We report that in rats retrieving spatial information, carbachol—induced IP accumulation strongly and transiently increased above values observed in handled controls and rats acquiring new information, and that this increase was profoundly inhibited by N-methyl-D-aspartate (NMDA). These results suggest that memory retrieval, rather than formation of a memory trace, is related to increased responsiveness of the hippocampal cholinergic system, and that formation of a new memory trace, which updates long-term memory, inhibits this cholinergic activation, possibly by a learning-associated increase in NMDA receptor activation. Moreover, the present study shows that the distinction between acquisition and retrieval processes can be demonstrated on both a behavioral and biochemical level.

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2019, Progress in Neuro-Psychopharmacology and Biological Psychiatry
Citation Excerpt :
All of the abovementioned neurotransmitters operate mainly through GP-coupled metabotropic receptors. The reactiveness of the receptor systems may be affected by various psychotropic drugs, including antidepressants, which are often prescribed for treatment of fear-related disorders, such as anxiety disorders (Nalepa et al., 1998; Nalepa and Vetulani, 1993, 1994; Popik et al., 1994). GPs have been classified into the following four main families: Gs, which stimulate adenylyl cyclase (AC); Gi and Go, which inhibit AC; Gq and G11, which stimulate phospholipase C beta (PLC); and G12, which modulates the activity of so-called small GPs, e.g., Rho.
Disturbances in fear-evoked signal transduction in the hippocampus (HP), the nuclei of the amygdala (AMY), and the prefrontal cortex (PFC) underlie anxiety-related disorders. However, the molecular mechanisms underlying these effects remain elusive. Heterotrimeric G proteins (GPs) are divided into the following four families based on the intracellular activity of their alpha subunit (Gα): Gα(s) proteins stimulate cyclic AMP (cAMP) generation, Gα(i/o) proteins inhibit the cAMP pathway, Gα(q/11) proteins increase the intracellular Ca⁺⁺ concentration and the inositol trisphosphate level, and Gα(12/13) proteins activate monomeric GP-Rho. In the present study, we assessed the effects of a fear memory procedure on the mRNA expression of the Gα subunits of all four GP families in the HP, AMY and PFC. C57BL/6 J mice were subjected to a fear conditioning (FC) procedure followed by a contextual or cued fear memory test (CTX-R and CS-R, respectively). Morphine (MOR, 1 mg/kg/ip) was injected immediately after FC to prevent the fear consolidation process. Real-time quantitative PCR was used to measure the mRNA expression levels of Gα subunits at 1 h after FC, 24 h after FC, and 1 h after the CTX-R or CS-R. In the HP, the mRNA levels of Gα(s), Gα(12) and Gα(11) were higher at 1 h after training. Gα(s) levels were slightly lower when consolidation was stabilized and after the CS-R. The mRNA levels of Gα(12) were increased at 1 h after FC, returned to control levels at 24 h after FC and increased again with the CTX-R. The increase in the Gα(11) level persisted at 24 h after FC and after CTX-R. In the AMY, no specific changes were induced by FC. In the PFC, CTX-R was accompanied by a decrease in Gα(i/o) mRNA levels; however, only Gα(i2) downregulation was prevented by MOR treatment. Hence, the FC-evoked changes in Gα mRNA expression were observed mainly in the HP and connected primarily to contextual learning. These results suggest that the activation of signaling pathways by Gα(s) and Gα(12) is required to begin the fear memory consolidation process in the HP, while signal transduction via Gα(11) is implicated in the maintenance of fear consolidation. In the PFC, the downregulation of Gα(i2) appears to be related to the contextual learning of fear.
Pharmacological induction of hemeoxygenase-1 activity attenuates intracerebroventricular streptozotocin induced neurocognitive deficit and oxidative stress in rats
2016, European Journal of Pharmacology
Citation Excerpt :
This excludes the possibility, which the locomotor activity per se may have contributed to the changes in spatial and non-spatial paradigms. Centrally, cholinergic system has been reported to play an important role in memory and cognitive functions (Butcher and Woolf, 1986; Everitt and Robbins, 1997; Haense et al., 2012; Miranda et al., 2003; Popik et al., 1994; Barker and Warburton, 2009). Acetylcholinesterase is the enzyme that hydrolyses acetylcholine into choline and acetate and acetylcholinesterase inhibitors have been proved to be beneficial in the treatment of cognitive disorders (Sarter and Parikh, 2005).
Under conditions of oxidative stress associated with neurodegenerative disorders, alterations in hemeoxygenase-1 (HO-1) activity have been reported. In the present study we have investigated the role of HO-1 pathway in intracerebroventricular (ICV) streptozotocin (STZ) induced neurocognitive deficits and oxidative stress in rats. STZ was infused ICV bilaterally (3 mg/Kg) on the alternate days in rats. Hemin was used as a pharmacological inducer of HO-1 activity and tin-protoporphyrin (SnPP) as HO-1 inhibitor. Hemin was administered with or without SnPP from day to 21 following 1st STZ infusion in rats. The cognitive functions were assessed by Morris water maze (MWM) and object recognition task (ORT) in rats. Biochemically, rat hippocampal and cortical brain homogenate was used to assess the levels of oxidative stress markers and acetylcholinesterase and HO-1 activity. Infusion of STZ caused significant elevation HO-1 activity on day 7 following 1st STZ infusion, however it was decreased on day 21, indicating its oxidative modification. Hemin caused significant elevation in HO-1 activity and attenuated STZ-induced oxidative stress. Moreover, hemin restored acetylcholinesterase activity and cognitive functions in STZ infused rats. Pre-administration of SnPP completely abrogated beneficial effects of hemin in STZ rats, indicating HO-1 dependency. The observed beneficial effects of hemin on spatial memory may be due to its ability to favorably modulate HO-1 pathway and antioxidant mechanisms.
Probucol mitigates streptozotocin-induced cognitive and biochemical changes in mice
2015, Neuroscience
Citation Excerpt :
Therefore, the use of the cholinesterase inhibitors is the most effective pharmacological approach for the symptomatic treatment of AD (Racchi et al., 2004). Cholinergic system in the hippocampus plays an important role in memory formation and retrieval (Popik et al., 1994; Carli et al., 2000). Pivotal role of cholinergic system in memory is further underlined by use of acetylcholine esterase inhibitors in AD to prevent memory decline (DeLaGarza, 2003).
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by synaptic loss and cognitive impairments. Although AD is the most prevalent aging-related neurodegenerative disease, therapeutic strategies remain palliative. Recent studies have shown that probucol presents neuroprotective effects in experimental models of neurodegenerative disease. The present study aimed to investigate the potential protective effects of probucol against streptozotocin (STZ)-induced cognitive impairment and hippocampal biochemical changes (oxidative stress-related parameters, acetylcholinesterase (AChE) activity, cholesterol levels and β-secretase (BACE) protein levels) in mice. Adult Swiss mice received STZ [150 μg/bilateral, i.c.v.], and treated daily with probucol (≅10 mg/kg/day, in drinking water, for 5 weeks,). Twenty-one days after i.c.v. administrations, STZ-infused animals displayed significant deficits in cognition (evaluated in the displaced and new object recognition tasks), which were paralleled by a significant increase in hippocampal AChE activity. Moreover, STZ-infused mice showed increased levels of BACE and decreased glutathione reductase (GR) activity in the hippocampus compared with the control group. Probucol treatment significantly protected against the behavioral and hippocampal biochemical changes induced by STZ. However, it was unable to prevent STZ-induced increase of hippocampal BACE levels and did not change hippocampal cholesterol levels. It is noteworthy that probucol treatment increased the glutathione peroxidase (GPx) activity per se independent of STZ injection. The present findings are the first to show that i.c.v. STZ infusions are able to increase hippocampal BACE expression. Moreover, the results also show that probucol can counteract STZ-induced cognitive impairments and biochemical parameters independently of potential modulator effects toward BACE levels. The study is the first to report the protective effects of probucol against STZ-induced biochemical hippocampal changes and behavioral impairments, rendering this compound a promising molecule for further pharmacological studies on the search for therapeutic strategies to treat or prevent AD.
Central angiotensin converting enzyme facilitates memory impairment in intracerebroventricular streptozotocin treated rats
2012, Behavioural Brain Research
Citation Excerpt :
This suggests that Ang II contributes to the ageing process by prompting mitochondrial dysfunction and blockade of RAS will reduce ROS and enhances mitochondrial content and function. Cholinergic system in the hippocampus plays an important role in memory formation and retrieval [25,26]. As reported in our previous studies [4,29,30,42], in this study also we found impaired cholinergic system as shown by increased acetylcholinesterase activity in STZ injected rat brain regions.
Preclinical and clinical studies indicated involvement of renin angiotensin system (RAS) in memory functions. However, exact role of RAS in cognition is still ambiguous. Our aim was to explore how angiotensin converting enzyme (ACE) modulates memory in experimental model of memory impairment. Memory deficit was induced by intracerebroventricular administration of streptozotocin (STZ, 3 mg/kg) in rats. Perindopril, an ACE inhibitor, was given for 21 days and memory function was evaluated by Morris water maze test. Cerebral blood flow (CBF) was measured by laser doppler flowmetry. The biochemical and expression studies were done in cortex and hippocampus of rat brain after the completion of behavioral studies. STZ caused impairment in memory along with significant reduction in CBF, ATP level and elevated oxidative and nitrosative stress. The activity and mRNA expression of acetylcholinesterase (AChE) and ACE were also increased in rat brain regions following STZ administration. However, serum ACE activity remained unaffected. Treatment with perindopril dose dependently improved memory by increasing energy metabolism and CBF. Perindopril also decreased oxidative and nitrosative stress, activity and mRNA expression of AChE and ACE in STZ treated rat. Further, ACE inhibition mitigated STZ induced neurodegeneration as observed in histopathological studies. Moreover, perindopril per se improved memory and CBF, decreased oxidative stress with no effect on AChE activity and expression. However, perindopril per se significantly reduced ACE activity but increased mRNA expression of ACE in rat brain. These results suggest that ACE occupies a pivotal role in STZ induced memory deficit thus implicating central RAS in cognition.
SP600125, a competitive inhibitor of JNK attenuates streptozotocin induced neurocognitive deficit and oxidative stress in rats
2010, Pharmacology Biochemistry and Behavior
Activated JNK has been reported to be located in nucleus in mild cases of Alzheimer's disease (AD), but is exclusively in cytoplasm in more advanced stages of AD and implicated in its pathogenesis, suggesting that activation and re-distribution of JNK correlate with the progress of AD. The present study was designed to investigate the role of JNK in intracerebroventricular streptozotocin (i.c.v. STZ) induced cognitive impairment and oxidative stress. Streptozotocin has been observed to impair learning and memory, increase oxidative–nitritive stress, induce cholinergic hypofunction and neuronal damage in rat brain. Chronic treatment with SP600125 from day 10 to 28 following i.c.v. STZ injections significantly improved spatial memory, attenuate oxidative–nitritive stress. In addition, significant increase in acetylcholinesterase activity and lactate dehydrogenase (LDH) levels was observed in the present model indicating cholinergic hypofunction and increase in neuronal cell damage. Whereas, SP600125 treatment significantly restored acetylcholinesterase activity and reduced LDH levels indicating restorative capacity of SP600125 with respect to cholinergic functions and preventing the neuronal damage. In line with previous report, the current study also supports the potential of JNK inhibition as a possible therapeutic strategy to ameliorate neurodegenerative disorders associated with oxidative stress and cognitive impairment.
Amelioration of intracerebroventricular streptozotocin induced cognitive dysfunction and oxidative stress by vinpocetine - a PDE1 inhibitor
2009, European Journal of Pharmacology
Enhancing cyclic nucleotides signaling by inhibition of phosphodiesterases (PDEs) is known to be beneficial in disorders associated with cognitive decline. The present study was designed to investigate the effect of vinpocetine (PDE1 inhibitor) on intracerebroventricular (i.c.v.) streptozotocin induced experimental sporadic dementia of Alzheimer's type. Infusion of streptozotocin impaired learning and memory, increased oxidative–nitritive stress and induced cholinergic hypofunction in rats. Chronic treatment with vinpocetine (5, 10 and 20 mg/kg i.p.) for 21 days following first i.c.v. streptozotocin infusion significantly improved learning and memory in Morris water maze and passive avoidance paradigms. Further, vinpocetine significantly reduced the oxidative–nitritive stress, as evidenced by decrease in malondialdehyde (MDA) and nitrite levels, and restored the reduced glutathione (GSH) levels. Significant increase in acetylcholinesterase activity and lactate dehydrogenase levels was observed in the present model indicating cholinergic hypofunction and increase in neuronal cell damage. Chronic treatment with vinpocetine also reduced significantly the increase in acetylcholinesterase activity and lactate dehydrogenase levels indicating restorative capacity of vinpocetine with respect to cholinergic functions and preventing the neuronal damage. The observed beneficial effects of vinpocetine on spatial memory may be due to its ability to favorably modulate cholinergic functions, prevent neuronal cell damage and possibly through its antioxidant mechanism also.

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¹: Present address and correspondence: National Institutes of Health, NIDDK/LN Bldg. 8, Room 111, Bethesda, MD, 20892, Fax: (301) 402-2872

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Retrieval associated cholinergic activity and its inhibition by memory updating

Abstract

Behavioural Brain Research

Behavioral and Neural Biology

Learning and Motivation

Neuroscience

Behavioural Brain Research

Neuroscience Letters

Science

Science

Nature

J Comp Physiol Psychol

Behavioral Neuroscience

Nature