Performance In Passive Avoidance Task Research Articles

0202 Sleep Deprivation: Cognitive Decline and Hippocampal Neuroinflammation

Abstract Introduction A highly conserved biological process, sleep is imperative for healthy brain function. Sleep deprivation (SD) disrupts cognition and increases susceptibility to neurological disorders. The first step to developing mitigation strategies, this study investigated mechanisms underlying sleep-induced cognitive impairment, including hippocampal neuroinflammation. Methods All animal activities were approved under an IACUC protocol. Male Sprague-Dawley rats (N = 50) underwent 120 h of SD. Novel Object Recognition (NOR) and Passive-Avoidance Task (PAT) assessed cognitive performance (n = 6-12), followed by humane euthanization. Protein analysis of hippocampal tissue was performed using immunohistochemistry (IHC, n = 3-6) and enzyme-linked immunoassay (ELISA, n = 8-13). Microglia (Iba-1 marker) and astrocyte (GFAP marker) populations were quantified using IHC and ImageJ. The ELISA V-PLEX assay was used to assess concentration of pro-/anti-inflammatory mediators. Results Tested 24 h after training, SD rats had significantly lower cognitive performance in NOR (p< 0.05) and PAT (p< 0.01). Percentage of Iba-1+ microglia in the stratum radiatum of CA1 (p< 0.05) and CA2 (p< 0.05) hippocampal subregions was higher among SD rats. This SD-induced increase in microglia was not found in the pyramidal layer of CA1/2/3 (p>0.05). There was no SD-associated change in percentage of GFAP+ astrocytes in any hippocampal subregion (p>0.05). ELISA analysis found SD rats had higher levels of pro-inflammatory chemokine ligand 1 (CXCL1, p< 0.05) and anti-inflammatory interleukin-10 (IL-10, p=0.07) in the hippocampus. Conclusion SD-induced cognitive impairment was associated with increased microglia presence in CA1/2 subregions of the hippocampus. Increased expression of hippocampal CXCL1 after SD indicates these CA1/2 microglia are pro-inflammatory, leading to neuroinflammation in regions that mediate declarative memory. Although IL-10 trended to increase after SD, this neuroprotective anti-inflammatory factor did not prevent SD-induced performance decline or microglia recruitment. Based on these findings, it is suggested that blocking pro-inflammatory microglia pathways in the CA1/2 may prevent SD-induced cognitive dysfunction. Support (if any) AFOSR grant 20RHCOR04

Vagus nerve stimulation-induced cognitive enhancement: Hippocampal neuroplasticity in healthy male rats

BackgroundVagus nerve stimulation (VNS) improves cognition in humans and rodents, but the effects of a single session of VNS on performance and plasticity are not well understood. ObjectiveBehavioral performance and hippocampal (HC) electrophysiology/neurotrophin expression were measured in healthy adult rats after VNS paired training to investigate changes in cognition and synaptic plasticity. MethodsPlatinum/iridium electrodes were surgically implanted around the left cervical branch of the VN of anesthetized male Sprague-Dawley rats (N = 47). VNS (100 μs biphasic pulses, 30 Hz, 0.8 mA) paired Novel Object Recognition (NOR)/Passive Avoidance Task (PAT) were assessed 24 h after training and post-mortem tissue was collected 48 h after VNS (N = 28). Electrophysiology recordings were collected using a microelectrode array system to assess functional effects on HC slices 90 min after VNS (N = 19). Sham received the same treatment without VNS and experimenters were blinded. ResultsStimulated rats exhibited improved performance in NOR (p < 0.05, n = 12) and PAT (p < 0.05, n = 14). VNS enhanced long-term potentiation (p < 0.05, n = 7–12), and spontaneous spike amplitude (p < 0.05, n = 7–12) and frequency (p < 0.05, n = 7–12) in the CA1. Immunohistochemical analysis found increased brain-derived neurotrophic factor expression in the CA1 (p < 0.05, n = 8–9) and CA2 (p < 0.01, n = 7–8). ConclusionThese findings suggest that our VNS parameters promote synaptic plasticity and target the CA1, which may mediate the positive cognitive effects of VNS. This study significantly contributes to a better understanding of VNS mediated HC synaptic plasticity, which may improve clinical utilization of VNS for cognitive enhancement.

Paeonol Ameliorates Cuprizone-Induced Hippocampal Demyelination and Cognitive Deficits through Inhibition of Oxidative and Inflammatory Events.

Multiple sclerosis (MS) is a chronic and inflammatory disorder of the central nervous system with autoimmune nature that is typified by varying degrees of demyelination and axonal damage. Paeonol is an active ingredient in some medicinal plants with anti-inflammatory and neuroprotective property. This study was conducted to reveal whether paeonol can alleviate hippocampal demyelination and cognitive deficits in cuprizone-induced murine model of demyelination as a model of MS. C57BL/6 mice received oral cuprizone (400mg/kg) for 6weeks, and paeonol was administered p.o. at two doses of 25 or 100mg/kg, starting from the second week post-cuprizone for 5weeks. After assessment of learning and memory in different tasks, oxidative stress and inflammation were evaluated besides immunohistochemical assessment of hippocampal myelin basic protein (MBP). Paeonol (100mg/kg) properly ameliorated cognitive deficits in Y maze, novel object discrimination (NOD) test, and Barnes maze with no significant improvement of performance in passive avoidance task. In addition, paeonol treatment at the higher dose was also associated with partial restoration of hippocampal level of oxidative stress and inflammatory markers including MDA, ROS, GSH, SOD, catalase, NF-kB, and TNF. Besides, paeonol improved MMP as an index of mitochondrial integrity and health and reduced MPO as a factor of neutrophil infiltration. Furthermore, paeonol treatment prevented hippocampal MBP immunoreactivity, indicating its prevention of demyelination. In conclusion, the current study showed the preventive effect of paeonol against cuprizone-induced demyelination and cognitive deficits through reversing most oxidative stress- and inflammation-related parameters in addition to its improvement of mitochondrial health.

Synergistic effects between CA1 mu opioid and dopamine D1-like receptors in impaired passive avoidance performance induced by hepatic encephalopathy in mice

Numerous investigations have indicated that hepatic encephalopathy (HE) alters the levels of various neurotransmitters. However, comprehensive data regarding the effects of CA1 opioidergic and dopaminergic (DAergic) systems on HE-induced amnesia are still lacking. Following intra-dorsal hippocampal (CA1) injection of mu opioid and dopamine D1- and D2-like receptors antagonists in male mice, one-trial step-down and hole-board paradigms were used to assess memory and exploratory behaviors, respectively. Our data demonstrated that HE impairs memory 24days after bile duct ligation (BDL). Furthermore, while the higher dose of DA D1-like receptor antagonist (SCH23390, 0.5μg/mouse) induced amnesia and anxiogenic-like behaviors, mu receptor antagonist (naloxone: 0.0125, 0.025 and 0.05μg/mouse) and DA D2-like receptor antagonist (sulpiride: 0.0625, 0.125 and 0.25μg/mouse) by themselves, could not exert an effect on memory performance in passive avoidance task. On the other hand, pre-test injection of all drugs reversed the HE-induced amnesia 24days after BDL, while having no effect on exploratory behaviors. Pre-test co-administration of the subthreshold dose SCH23390 (0.25μg/mouse) and sulpiride (0.0625μg/mouse) or naloxone (0.0125μg/mouse) could likewise reverse the BDL-induced amnesia. However, when the subthreshold sulpiride plus naloxone were co-administered, BDL-induced amnesia was not blocked. Memory performance is impaired 24days post BDL and CA1 mu opioid and DA D1-like receptors antagonist synergistic effects are likely involved in this phenomenon.

Protective Efficacy of Coenzyme Q10 Against DDVP-Induced Cognitive Impairments and Neurodegeneration in Rats

The present study was carried out to elucidate the effects of coenzyme Q(10) (CoQ(10)) against cognitive impairments induced by dichlorvos (DDVP). We have previously shown organophosphate, DDVP-induced impairments in neurobehavioral indices viz. rota rod, passive avoidance, and water maze tests. In addition to this, we have also reported that chronic DDVP exposure leads to decreased mitochondrial electron transfer activities of cytochrome oxidase along with altered mitochondrial complexes I-III activity. Administration of CoQ(10) (4.5 mg/kg, i.p. for 12 weeks prior to DDVP administration daily) to DDVP-treated rats improved cognitive performance in passive avoidance task and Morris water maze test. Furthermore, CoQ(10) treatment also reduced oxidative stress (as evident by reduced malondialdehyde, decreased ROS and increased Mn-SOD activity) in DDVP-treated rats' hippocampus region, along with enhanced activity of complexes I-III and complex IV. Electron microscope studies of rat hippocampus mitochondria revealed that CoQ(10) administration leads to near normal physiology of mitochondria with well-defined cristae compared with DDVP-treated animals where enlarged mitochondria with distorted cristae are observed. CoQ(10) administration also attenuated neuronal damage in hippocampus as evident from histopathological studies. These results demonstrate the beneficial effects of CoQ(10) against organophosphate-induced cognitive impairments and hippocampal neuronal degeneration.

Beneficial effects of pioglitazone on cognitive impairment in MPTP model of Parkinson's disease

The present study was carried out to elucidate the beneficial effect of pioglitazone in cognitive impairment induced by bilateral infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in substantia nigra pars compacta (SNc) in rats, a model of Parkinson's disease. MPTP-lesioned rats showed poor cognitive performance in both passive avoidance task and cued version of the Morris water maze test. This deficit in learning and memory was found to be associated with oxidative stress. Chronic administration of pioglitazone (10 and 30 mg/kg, p.o., starting 5 days prior to MPTP administration and then for next 30 days) in MPTP-lesioned rats improved cognitive performance in passive avoidance task and cued version of the Morris water maze test. Furthermore, pioglitazone treatment also reduced oxidative stress (as evident by reduced malondialdehyde and increased glutathione levels). These results demonstrate the beneficial effects of pioglitazone on cognitive impairment in MPTP induced Parkinson's disease in rats.

Enhanced novelty‐induced activity, reduced anxiety, delayed resynchronization to daylight reversal and weaker muscle strength in tenascin‐C‐deficient mice

Tenascin-C (TNC) is an extracellular matrix protein with multiple and important functions during development and in the adult. We here present a study on the behaviour of TNC-deficient (knockout, KO) mice. Longitudinal experiments including tests for circadian activity, exploration, state and trait anxiety, motor coordination and cognition were performed. KO mice showed increased reactivity to explore a novel environment and decreased anxiety. Spontaneous circadian activity was unaffected, but KO mice showed delayed resynchronization to daylight reversal. TNC deficiency caused weaker muscle strength, whereas gait, coordination and motor learning were unaltered. Short- and long-term memory in the fear conditioning task and working memory in the spontaneous alternation test were normal in KO mice. KO mice showed impaired memory recall in the step-down, but not in the step-through, passive avoidance task. Ethological observation of mice behaviour and principal component analyses indicated that the higher novelty- and stress-induced active responses of KO mice account for their poorer performance in passive avoidance tasks, whereas cognitive abilities are unaltered. The present study extends and corrects previous results, and is an example of how an ethological approach allows a precise description and interpretation of the behavioural alterations of mutant mice.

Glutamate antagonists attenuate the action of NC-1900, a vasopressin fragment analog, on passive avoidance task performance in mice

To examine the relationship between glutamate receptors and the action of NC-1900 on a step-through passive avoidance (PA) task in mice, MK-801, an NMDA receptor blocker, and ( S)-4-carboxyphenylglycine (4CPG), a group I metabotropic receptor antagonist, were administered intraventricularly (i.c.v.) singly or as co-injections. The i.c.v. injection of MK-801 (0.8 μg) or 4CPG (2 μg) decreased the latency on the PA task. NC-1900 (1 ng/kg, subcutaneously (s.c.)) alone prolonged the latency on the retention trial in the PA task. MK-801 (0.2 and 0.8 μg) or 4CPG (0.5 and 2 μg) significantly inhibited the action of NC-1900, while the s.c. injection of NC-1900 did not affect latency in mice that received i.c.v. co-injection of MK-801 and 4CPG at any of the doses tested. These results suggest that glutamate receptors participate in the action of NC-1900 on learning and memory in PA task performance.

Ameliorative and Exacerbating Effects of [pGlu4,Cyt6]AVP(4–9) on Impairment of Step-Through Passive Avoidance Task Performance by Group II Metabotropic Glutamate Receptor-Related Drugs in Mice

To examine the effect of the arginine-vasopressin fragment, [pGlu4,Cyt6]AVP(4–9) (AVP4–9), on group II metabotropic glutamate receptor (mGluR2/3) agonist and antagonist induced impairment of passive avoidance (PA) task performance, AVP4–9 or phorbol 12-myristate 13-acetate (PMA) was administered in the presence of mGluR2/3-related drugs that induced the impairment of the step-through-type PA task performance. The PA task performance was evaluated in terms of the latency (the time that elapsed prior to entry into the dark compartment) at 24 h after the electrical stimulation. The subcutaneous injection of AVP4–9 at 1 μg/kg had the greatest facilitative effect on the performance, and the facilitative effect of AVP4–9 was inhibited by NPC-15437, a specific protein kinase C (PKC) inhibitor. The injection of AVP4–9 ameliorated PA task performance impairment induced by DCG-IV, an mGluR2/3 agonist. Intracisternal injection of PMA, a PKC activator, also ameliorated the DCG-IV-induced impairment. High doses of AVP4–9 exacerbated the PA task performance impairment induced by LY341495 (an mGluR2/3 antagonist), and PMA injection (1 μg) also exacerbated the impairment induced by the antagonist. These results suggest that an increase in the activity of the PKC-signaling pathway may not always facilitate PA task performance; therefore, AVP4–9 can either enhance or inhibit memory performance in mice.

Dietary Docosahexaenoic Acid Increases Cerebral Acetylcholine Levels and Improves Passive Avoidance Performance in Stroke-Prone Spontaneously Hypertensive Rats

We have recently shown that inferior performance in passive avoidance task is accompanied with decreased hippocampal choline (Ch) in stroke-prone spontaneously hypertensive rats (SHRSP) compared with normotensive control Wistar–Kyoto rats (WKY). We also reported that dietary docosahexaenoic acid (DHA) suppresses the development of hypertension and stroke-related behavioral changes, resulting in the prolongation of the life span of SHRSP. In this study, we examined the effect of dietary DHA on the cerebral acetylcholine (ACh) levels and learning performance in passive avoidance tasks in SHRSP. The arachidonic acid decreased and the DHA increased in plasma lipids dose dependently with dietary DHA treatments, which decreased the systolic blood pressure in SHRSP. Dietary DHA significantly restored the significantly inferior learning performance in passive avoidance response observed in control SHRSP (DHA 0%). Furthermore, the hippocampal ACh levels were correlated positively with the total response latency in passive avoidance tasks. These results suggest that cholinergic dysfunction in the brain of control SHRSP is responsible, at least in part, for the impaired learning ability and the dietary DHA ameliorates this performance failure.

Nicotine reverses scopolamine-induced impairment of performance in passive avoidance task in rats through its action on the dopaminergic neuronal system

Interest has recently focused on tobacco and/or nicotine in relation to senile dementia of the Alzheimer type because the population of patients with this disease among tobacco smokers is significantly smaller than in nonsmokers. We investigated whether, in relation to the dopaminergic neuronal system, nicotine was effective in ameliorating the impairment of performance in passive avoidance tasks in rats induced by scopolamine, an inhibitor of muscarinic acetylcholine receptors. Scopolamine and nicotine were coadministered to rats 30 min before the acquisition trial. Some rats received scopolamine alone; they should much shorter step-through latency (STL) than the control group in the retention test. Nicotine significantly prolonged the decreased STL induced by scopolamine. The effects of nicotine were inhibited by the preadministration of mecamylamine, SCH 23390, and (−)sulpiride, which are nicotinic acetylcholine, D 1, and D 2 receptor antagonists, respectively. These results suggest that nicotine, by activating the nicotinic acetylcholinergic and dopaminergic neuronal systems, ameliorates the impairment of performance in the passive avoidance task induced by a muscarinic acetylcholine receptor blocker.

P197 acamprosate effect on performance of passive avoidance tasks in chronically ethanol treated rats - preliminary report

P197 acamprosate effect on performance of passive avoidance tasks in chronically ethanol treated rats - preliminary report

Methyl mercury during late gestation affects temporarily the development of cortical muscarinic receptors in rat offspring.

Pregnant Sprague-Dawley rats were treated by gavage with a single dose of 8 mg/kg of methyl mercury on gestational day 15. Offspring of control and treated rats were killed at 14, 21 and 60 days of age. The binding characteristics of muscarinic receptors labelled in cortical membrane preparation by 3H-L-quinuclidinyl benzilate were studied together with the assessment of mercury level in the same brain area. Furthermore, the performance in passive avoidance tasks was evaluated in 8 weeks old rats. Perinatal exposure to methyl mercury significantly reduced the maximum number of muscarinic receptors (Bmax) in the brain of 14 (53%) and 21 day old rats (21%), while this change was no more present in 60 day old rats. This phenomenon seems to be strictly related to the presence of mercury in the cortex since it disappeared with the normalization of mercury levels in the brain. Despite the recovery of muscarinic receptor densities in methyl mercury exposed rats at 8 weeks of age, the avoidance latency was reduced in passive avoidance test as an indication of learning and memory deficits in these animals. Results from this study indicate that prenatal methyl mercury exposure induces latent cognitive dysfunction which does not seem to be related to transient muscarinic receptor alteration found in the early period of postnatal life.

Different behavioral deficits are induced by anoxia/hypoxia in neonatal and senescent rats: blockade by MK-801

Rats exposed on their first postnatal day to 100% nitrogen for 25 min developed hyperactivity and lower performance in passive avoidance task during development. Administration of MK-801 (0.5 mg/kg i.p.) 1 h before anoxia or (0.25 and 0.5 mg/kg) 1 h after completely reversed this behavioral impairment. Senescent rats (24-26 months) exposed to hypoxia (92% N2 + 8% O2) for 5 h failed in their performance in C.A.R., 30 days later. Pretreatment with MK-801 (1 mg/kg i.p.) completely reversed this impairment. These data suggest that activation of endogenous NMDA receptors produces different behavioral consequences in neonatal and senescent rats and that MK-801 administration close to exposure of animals to anoxia or hypoxia can prevent such damage, thus preventing behavioral impairments in postnatal as well as in senescent rats.