566 Vesmír 96, říjen 2017 www.vesmir.cz 567 téma-mozek hiPokamPus je párová struktura ležící pod ... more 566 Vesmír 96, říjen 2017 www.vesmir.cz 567 téma-mozek hiPokamPus je párová struktura ležící pod hlavními mozkovými polokoulemi. Vývojově se jedná o evolučně starou moz-kovou kůru, které byla překryta korovými oblastmi. U člověka má tvar mořského ko-níka (lat. Hippocampus), proto jeho označení, a u hlodavců, třeba u modelového druhu laboratorního potkana (Rattus norvegicus), se dá jeho tvar připodobnit k "rohlíku loupá-ku". U člověka je hipokampus v poměru ke hmotě celého mozku výrazně menší než u hlodavců, avšak neméně důležitý. Jde o strukturu velmi vrstevnatou, zastáva-jící mnoho funkcí. Kromě gyrus dentatus (zubatý závit je pouze pokusem o vtip, český ekvivalent prozatím neexistuje) jde hlavně o oblasti Ammonova rohu. Různé důležité funkce zde zajišťuje řada buněčných typů. Hlavními "nosiči infor-mace" jsou granulární (zrnité) buňky gyrus dentatus a pyramidové neurony (též zvané principiální). Naprosto zásadní je i role tlumivých interneuronů (vmezeřených bu-něk). Ty se významně podílejí na početných procesech, především tím, že svojí tlumivou aktivitou udržují správný poměr signálu vůči šumu. HIPOKAMPuS A PAMěť Historicky se nejprve soudilo, že se hi-pokampus účastní čichového vnímání, předpokládalo se totiž jeho přímé spojení s čichovým lalokem. Obě struktury však přímo spojeny nejsou. Často o něm badatelé uvažovali v souvislosti s emocemi. Pozdější výzkumy ukázaly, že zde hraje klíčovou roli jiná oblast mozku, amygdala. Nakonec vědci prokázali, že hipokampus, obzvláště jeho zadní část, je důležitým centrem učení a paměti. V roce 1957 badatelé William Scoville a Brenda Milnerová popsali případ pacienta Henryho Gustava Molaisona, který trpěl nezvladatelnou epilepsií. Tyto případy se dodnes někdy řeší vyjmutím části mozkové tkáně, která obsahuje epileptické ložisko, a to v případě, že daná mozková oblast není životně nezbytná. A tak byla panu Molai-sonovi odoperována velká část středního spánkového laloku včetně obou hipokampů. Epileptické záchvaty se tím podařilo zvlád-nout, objevil se však nečekaný poznatek. Tento člověk nebyl schopen uložit do své paměti nové vzpomínky. V nemocnici, kde se léčil, se například každý den ráno znovu seznamoval se členy ošetřujícího personálu, jako by je nikdy nepotkal. Několikrát oplakal smrt svého oblíbeného strýce a události v denním tisku byly pro něj vždy horkou novinkou. Neuropsychologické vyšetřování tohoto pacienta prokázalo, že má narušené formování tzv. deklarativní paměti (vzpo-mínky na fakta a události). Procedurální paměť, která představuje motorické doved-nosti, kupodivu byla zachována. Například byl schopen se naučit obkreslovat tvary v zrcadle, ale nebyl si vůbec nikdy vědom, že se tuto úlohu učil. Rovněž si uchoval vzpomínky na fakta a události ve velmi vzdálené minulosti, avšak nové tvořit nedokázal (tento stav je označován jako anterográdní a časově stup-ňovaná retrográdní amnézie). I další studie na pacientech s poškozením či operačním odstraněním hipokampu potvrdily fakt, že u lidí se takové narušení projeví zejména ztrátou paměti pro události (epizodická pa-měť), zatímco inteligence, řeč, motorické do-vednosti, jazyková plynulost a další funkce zůstanou nepostiženy a pacienti velmi často po operaci žijí podobně jako pan Molaison. Případy jeho a dalších pacientů tak jedno-značně ukázaly na roli hipokampu v dekla-rativní paměti, a to zejména v epizodické paměti pro události. Je logické, že pro existenci paměti, tedy trvalé změny v chování či prožívání, bude nezbytná nějaká dlouhodobá změna v signalizaci v nervové soustavě. Tu si lze v nejjednodušším představit například jako zvýšený přenos informace mezi dvěma buňkami propojenými synapsí. Již v roce 1949 badatel Donald Hebb postuloval v knize Organizace chování následující hypotézu: Pokud jsou dvě nervové buňky zapojené synapsí současně aktivní, dochází v nich k určitým metabolickým či růsto-vým změnám, které vedou k tomu, že si oba neurony následně předávají informaci účinněji. V sedmdesátých letech minulého století badatel David Marr zase navrhl způ-sob, jakým se odehrává vybavení vzpomín-ky-aktivací distribuovaných výpočetních jednotek (neuronů), které jsou vzájemně propojeny, a tyto spoje mezi nimi učením posíleny. Následně by k vybavení informa-ce měla postačit částečná aktivace někte-rých těchto výpočetních jednotek. Přestože Marrův koncept vybavení paměťové stopy není zcela přesný, položil základ pro po-chopení role vztahu synaptické plasticity a paměti. V roce 1973 badatelé Tim Bliss a Ter-je Lømo z laboratoře Pera Andersena ve švédském Stockholmu prokázali zajímavý fenomén-pokud tetanicky dráždili vstupní dráhu do hipokampu u anestezovaného králíka, bylo u něj možné zjistit významné zvýšení synaptických odpovědí na jednotli-vé pulzy. Tento jev dostal jméno dlouhodobá potenciace. V průběhu dalších desetiletí se badatelé pokoušeli potvrdit vztah mezi dlouhodobou potenciací a pamětí různými způsoby, avšak důkazy byly stále nepřímé. Průlomový byl rok 2006, kdy původem česká badatelka Eva Pašťalková prokázala, že blokáda specific-kého enzymu, klíčového pro dlouhodobou potenciaci, vymaže paměťovou stopu. Sho-dou okolností ve stejný okamžik Jonathan Whitlock a jeho kolegové ukázali, že učení se paměťové úloze přímo vede k navození dlouhodobé potenciace. Badatelé toto téma i nadále intenzivně studují, avšak hypotéza o tom, že dlouhodobá potenciace v hipokam-pu je podkladem paměti, je dnes velmi silná. HIPOKAMPuS A PROSTOR V roce 1973 badatelé John O'Keefe a Jo-nathan Dostrovsky zjistili, že v hipokampu laboratorních potkanů se nacházejí neuro-ny, které spouštějí salvy vzruchů, pokud se potkan ocitl na nějakém místě experimen-tálního prostoru. Jako by zvířeti říkaly: hipokampus-náš "atlas světa" Jak je hipokampus "zkonstruován"? Jaké procesy v něm probíhají? Jaká onemocnění jej zasahují? dnes už víme mnohé, například to, že se významně podílí na učení a paměti.
Infection during the prenatal or neonatal stages of life is considered one of the major risk fact... more Infection during the prenatal or neonatal stages of life is considered one of the major risk factors for the development of mental diseases such as schizophrenia or autism. However, the impacts of such an immune challenge on adult behavior are still not clear. In our study, we used a model of early postnatal immune activation by the application of bacterial endotoxin lipopolysaccharide (LPS) to rat pups at a dose of 2 mg/kg from postnatal day (PD) 5 to PD 9. In adulthood, the rats were tested in a battery of tasks probing various aspects of behavior: spontaneous activity (open field test), social behavior (social interactions and female bedding exploration), anxiety (elevated plus maze), cognition (active place avoidance in Carousel) and emotional response (ultrasonic vocalization recording). Moreover, we tested sensitivity to acute challenge with MK-801, a psy-chotomimetic drug. Our results show that the application of LPS led to increased self-grooming in the female bedding exploration test and inadequate emotional reactions in Carousel maze displayed by ultrasonic vocali-zations. However, it did not have serious consequences on exploration, locomotion, social behavior or cognition. Furthermore, exposition to MK-801 did not trigger social or cognitive deficits in the LPS-treated rats. We conclude that the emotional domain is the most sensitive to the changes induced by neonatal immune activation in rats, including a disrupted response to novel and stressful situations in early adulthood (similar to that observed in human patients suffering from schizophrenia or autism), while other aspects of tested behavior remain unaffected .
Rationale There is a persistent pressing need for valid animal models of cognitive and mnemonic d... more Rationale There is a persistent pressing need for valid animal models of cognitive and mnemonic disruptions (such as seen in Alzheimer's disease and other dementias) usable for preclinical research. Objectives We have set out to test the validity of administration of biperiden, an M1-acetylcholine receptor antagonist with central selectivity, as a potential tool for generating a fast screening model of cognitive impairment, in outbred Wistar rats. Methods We used several variants of the Morris water maze task: (1) reversal learning, to assess cognitive flexibility, with probe trials testing memory retention; (2) delayed matching to position (DMP), to evaluate working memory; and (3) Bcounter-balanced acquisition,^to test for possible anomalies in acquisition learning. We also included a visible platform paradigm to reveal possible sensorimotor and motivational deficits. Results A significant effect of biperiden on memory acquisition and retention was found in the counterbalanced acquisition and probe trials of the counterbalanced acquisition and reversal tasks. Strikingly, a less pronounced deficit was observed in the DMP. No effects were revealed in the reversal learning task. Conclusions Based on our results, we do not recommend biperiden as a reliable tool for modeling cognitive impairment.
The discoordination hypothesis of schizophrenia posits discoordination of neural activity as the ... more The discoordination hypothesis of schizophrenia posits discoordination of neural activity as the central mechanism that underlies some psychotic symptoms (including 'hallmark' cognitive symptoms) of schizophrenia. To test this proposition, we studied the activity of hippocampal neurons in urethane anesthetized Long Evans rats after 0.15 mg/kg dizocilpine (MK-801), an N-Methyl-D-aspartate (NMDA) glutamate receptor antagonist, which can cause psychotic symptoms in humans and cognitive control impairments in animals. We observed that MK-801 altered the temporal coordination, but not rate, of neuronal firing. Coactivation between neurons increased , driven primarily by increased coincident firing of cell pairs that did not originally fire together before MK-801 injection. Increased pairwise coactivation manifested as disorganized discharge on the level of neuronal ensembles, which in turn could lead to disorganization in information processing. Disorganization of neuronal activity after a psychotomimetic dose of MK-801 supports the discoordination hypothesis of psychosis.
Adult neurogenesis in the dentate gyrus adds a substantial number of new functional neurons to th... more Adult neurogenesis in the dentate gyrus adds a substantial number of new functional neurons to the hip-pocampus network in rodents. To date, however, the function of these new granule cells remains unclear. We conducted an experiment to assess the contribution of adult neurogenesis in the dentate gyrus to acquisition and reversal learning in a task that predominantly requires generalization of a rule. Young adult male Long-Evans rats were repeatedly administered either a cytostatic temozolomide or saline for a period of four weeks (3 injections per week). Post treatment, animals were injected with bromod-eoxyuridine to quantify adult neurogenesis in the dentate gyrus. For behavioral assessment we used hippocampus-dependent active place avoidance with reversal in a Carousel maze. Animals first learned to avoid a 60°sector on the rotating arena. Afterwards, sector was relocated to the opposite side of the rotating arena (reversal). The administration of temozolomide significantly improved the reversal performance compared to saline-treated rats. Our results suggest a significant, level-dependent, improvement of reversal learning in animals with reduced adult neurogenesis in hippocampus.
Muscarinic acetylcholine receptors (mAChRs) have been found to regulate many diverse functions, r... more Muscarinic acetylcholine receptors (mAChRs) have been found to regulate many diverse functions, ranging from motivation and feeding to spatial navigation, an important and widely studied type of cognitive behavior. Systemic administration of non-selective antagonists of mAChRs, such as scopolamine or atropine, have been found to have adverse effects on a vast majority of place navigation tasks. However, many of these results may be potentially confounded by disruptions of functions other than spatial learning and memory. Although studies with selective antimuscarinics point to mutually opposite effects of M1 and M2 receptors, their particular contribution to spatial cogni-tion is still poorly understood, partly due to a lack of truly selective agents. Furthermore, constitutive knockouts do not always support results from selective antagonists. For modeling impaired spatial cognition, the scopolamine-induced amnesia model still maintains some limited validity, but there is an apparent need for more targeted approaches such as local intracerebral administration of antagonists, as well as novel techniques such as optogenetics focused on cholinergic neurons and chemogenetics aimed at cells expressing metabotropic mAChRs.
566 Vesmír 96, říjen 2017 www.vesmir.cz 567 téma-mozek hiPokamPus je párová struktura ležící pod ... more 566 Vesmír 96, říjen 2017 www.vesmir.cz 567 téma-mozek hiPokamPus je párová struktura ležící pod hlavními mozkovými polokoulemi. Vývojově se jedná o evolučně starou moz-kovou kůru, které byla překryta korovými oblastmi. U člověka má tvar mořského ko-níka (lat. Hippocampus), proto jeho označení, a u hlodavců, třeba u modelového druhu laboratorního potkana (Rattus norvegicus), se dá jeho tvar připodobnit k "rohlíku loupá-ku". U člověka je hipokampus v poměru ke hmotě celého mozku výrazně menší než u hlodavců, avšak neméně důležitý. Jde o strukturu velmi vrstevnatou, zastáva-jící mnoho funkcí. Kromě gyrus dentatus (zubatý závit je pouze pokusem o vtip, český ekvivalent prozatím neexistuje) jde hlavně o oblasti Ammonova rohu. Různé důležité funkce zde zajišťuje řada buněčných typů. Hlavními "nosiči infor-mace" jsou granulární (zrnité) buňky gyrus dentatus a pyramidové neurony (též zvané principiální). Naprosto zásadní je i role tlumivých interneuronů (vmezeřených bu-něk). Ty se významně podílejí na početných procesech, především tím, že svojí tlumivou aktivitou udržují správný poměr signálu vůči šumu. HIPOKAMPuS A PAMěť Historicky se nejprve soudilo, že se hi-pokampus účastní čichového vnímání, předpokládalo se totiž jeho přímé spojení s čichovým lalokem. Obě struktury však přímo spojeny nejsou. Často o něm badatelé uvažovali v souvislosti s emocemi. Pozdější výzkumy ukázaly, že zde hraje klíčovou roli jiná oblast mozku, amygdala. Nakonec vědci prokázali, že hipokampus, obzvláště jeho zadní část, je důležitým centrem učení a paměti. V roce 1957 badatelé William Scoville a Brenda Milnerová popsali případ pacienta Henryho Gustava Molaisona, který trpěl nezvladatelnou epilepsií. Tyto případy se dodnes někdy řeší vyjmutím části mozkové tkáně, která obsahuje epileptické ložisko, a to v případě, že daná mozková oblast není životně nezbytná. A tak byla panu Molai-sonovi odoperována velká část středního spánkového laloku včetně obou hipokampů. Epileptické záchvaty se tím podařilo zvlád-nout, objevil se však nečekaný poznatek. Tento člověk nebyl schopen uložit do své paměti nové vzpomínky. V nemocnici, kde se léčil, se například každý den ráno znovu seznamoval se členy ošetřujícího personálu, jako by je nikdy nepotkal. Několikrát oplakal smrt svého oblíbeného strýce a události v denním tisku byly pro něj vždy horkou novinkou. Neuropsychologické vyšetřování tohoto pacienta prokázalo, že má narušené formování tzv. deklarativní paměti (vzpo-mínky na fakta a události). Procedurální paměť, která představuje motorické doved-nosti, kupodivu byla zachována. Například byl schopen se naučit obkreslovat tvary v zrcadle, ale nebyl si vůbec nikdy vědom, že se tuto úlohu učil. Rovněž si uchoval vzpomínky na fakta a události ve velmi vzdálené minulosti, avšak nové tvořit nedokázal (tento stav je označován jako anterográdní a časově stup-ňovaná retrográdní amnézie). I další studie na pacientech s poškozením či operačním odstraněním hipokampu potvrdily fakt, že u lidí se takové narušení projeví zejména ztrátou paměti pro události (epizodická pa-měť), zatímco inteligence, řeč, motorické do-vednosti, jazyková plynulost a další funkce zůstanou nepostiženy a pacienti velmi často po operaci žijí podobně jako pan Molaison. Případy jeho a dalších pacientů tak jedno-značně ukázaly na roli hipokampu v dekla-rativní paměti, a to zejména v epizodické paměti pro události. Je logické, že pro existenci paměti, tedy trvalé změny v chování či prožívání, bude nezbytná nějaká dlouhodobá změna v signalizaci v nervové soustavě. Tu si lze v nejjednodušším představit například jako zvýšený přenos informace mezi dvěma buňkami propojenými synapsí. Již v roce 1949 badatel Donald Hebb postuloval v knize Organizace chování následující hypotézu: Pokud jsou dvě nervové buňky zapojené synapsí současně aktivní, dochází v nich k určitým metabolickým či růsto-vým změnám, které vedou k tomu, že si oba neurony následně předávají informaci účinněji. V sedmdesátých letech minulého století badatel David Marr zase navrhl způ-sob, jakým se odehrává vybavení vzpomín-ky-aktivací distribuovaných výpočetních jednotek (neuronů), které jsou vzájemně propojeny, a tyto spoje mezi nimi učením posíleny. Následně by k vybavení informa-ce měla postačit částečná aktivace někte-rých těchto výpočetních jednotek. Přestože Marrův koncept vybavení paměťové stopy není zcela přesný, položil základ pro po-chopení role vztahu synaptické plasticity a paměti. V roce 1973 badatelé Tim Bliss a Ter-je Lømo z laboratoře Pera Andersena ve švédském Stockholmu prokázali zajímavý fenomén-pokud tetanicky dráždili vstupní dráhu do hipokampu u anestezovaného králíka, bylo u něj možné zjistit významné zvýšení synaptických odpovědí na jednotli-vé pulzy. Tento jev dostal jméno dlouhodobá potenciace. V průběhu dalších desetiletí se badatelé pokoušeli potvrdit vztah mezi dlouhodobou potenciací a pamětí různými způsoby, avšak důkazy byly stále nepřímé. Průlomový byl rok 2006, kdy původem česká badatelka Eva Pašťalková prokázala, že blokáda specific-kého enzymu, klíčového pro dlouhodobou potenciaci, vymaže paměťovou stopu. Sho-dou okolností ve stejný okamžik Jonathan Whitlock a jeho kolegové ukázali, že učení se paměťové úloze přímo vede k navození dlouhodobé potenciace. Badatelé toto téma i nadále intenzivně studují, avšak hypotéza o tom, že dlouhodobá potenciace v hipokam-pu je podkladem paměti, je dnes velmi silná. HIPOKAMPuS A PROSTOR V roce 1973 badatelé John O'Keefe a Jo-nathan Dostrovsky zjistili, že v hipokampu laboratorních potkanů se nacházejí neuro-ny, které spouštějí salvy vzruchů, pokud se potkan ocitl na nějakém místě experimen-tálního prostoru. Jako by zvířeti říkaly: hipokampus-náš "atlas světa" Jak je hipokampus "zkonstruován"? Jaké procesy v něm probíhají? Jaká onemocnění jej zasahují? dnes už víme mnohé, například to, že se významně podílí na učení a paměti.
Infection during the prenatal or neonatal stages of life is considered one of the major risk fact... more Infection during the prenatal or neonatal stages of life is considered one of the major risk factors for the development of mental diseases such as schizophrenia or autism. However, the impacts of such an immune challenge on adult behavior are still not clear. In our study, we used a model of early postnatal immune activation by the application of bacterial endotoxin lipopolysaccharide (LPS) to rat pups at a dose of 2 mg/kg from postnatal day (PD) 5 to PD 9. In adulthood, the rats were tested in a battery of tasks probing various aspects of behavior: spontaneous activity (open field test), social behavior (social interactions and female bedding exploration), anxiety (elevated plus maze), cognition (active place avoidance in Carousel) and emotional response (ultrasonic vocalization recording). Moreover, we tested sensitivity to acute challenge with MK-801, a psy-chotomimetic drug. Our results show that the application of LPS led to increased self-grooming in the female bedding exploration test and inadequate emotional reactions in Carousel maze displayed by ultrasonic vocali-zations. However, it did not have serious consequences on exploration, locomotion, social behavior or cognition. Furthermore, exposition to MK-801 did not trigger social or cognitive deficits in the LPS-treated rats. We conclude that the emotional domain is the most sensitive to the changes induced by neonatal immune activation in rats, including a disrupted response to novel and stressful situations in early adulthood (similar to that observed in human patients suffering from schizophrenia or autism), while other aspects of tested behavior remain unaffected .
Rationale There is a persistent pressing need for valid animal models of cognitive and mnemonic d... more Rationale There is a persistent pressing need for valid animal models of cognitive and mnemonic disruptions (such as seen in Alzheimer's disease and other dementias) usable for preclinical research. Objectives We have set out to test the validity of administration of biperiden, an M1-acetylcholine receptor antagonist with central selectivity, as a potential tool for generating a fast screening model of cognitive impairment, in outbred Wistar rats. Methods We used several variants of the Morris water maze task: (1) reversal learning, to assess cognitive flexibility, with probe trials testing memory retention; (2) delayed matching to position (DMP), to evaluate working memory; and (3) Bcounter-balanced acquisition,^to test for possible anomalies in acquisition learning. We also included a visible platform paradigm to reveal possible sensorimotor and motivational deficits. Results A significant effect of biperiden on memory acquisition and retention was found in the counterbalanced acquisition and probe trials of the counterbalanced acquisition and reversal tasks. Strikingly, a less pronounced deficit was observed in the DMP. No effects were revealed in the reversal learning task. Conclusions Based on our results, we do not recommend biperiden as a reliable tool for modeling cognitive impairment.
The discoordination hypothesis of schizophrenia posits discoordination of neural activity as the ... more The discoordination hypothesis of schizophrenia posits discoordination of neural activity as the central mechanism that underlies some psychotic symptoms (including 'hallmark' cognitive symptoms) of schizophrenia. To test this proposition, we studied the activity of hippocampal neurons in urethane anesthetized Long Evans rats after 0.15 mg/kg dizocilpine (MK-801), an N-Methyl-D-aspartate (NMDA) glutamate receptor antagonist, which can cause psychotic symptoms in humans and cognitive control impairments in animals. We observed that MK-801 altered the temporal coordination, but not rate, of neuronal firing. Coactivation between neurons increased , driven primarily by increased coincident firing of cell pairs that did not originally fire together before MK-801 injection. Increased pairwise coactivation manifested as disorganized discharge on the level of neuronal ensembles, which in turn could lead to disorganization in information processing. Disorganization of neuronal activity after a psychotomimetic dose of MK-801 supports the discoordination hypothesis of psychosis.
Adult neurogenesis in the dentate gyrus adds a substantial number of new functional neurons to th... more Adult neurogenesis in the dentate gyrus adds a substantial number of new functional neurons to the hip-pocampus network in rodents. To date, however, the function of these new granule cells remains unclear. We conducted an experiment to assess the contribution of adult neurogenesis in the dentate gyrus to acquisition and reversal learning in a task that predominantly requires generalization of a rule. Young adult male Long-Evans rats were repeatedly administered either a cytostatic temozolomide or saline for a period of four weeks (3 injections per week). Post treatment, animals were injected with bromod-eoxyuridine to quantify adult neurogenesis in the dentate gyrus. For behavioral assessment we used hippocampus-dependent active place avoidance with reversal in a Carousel maze. Animals first learned to avoid a 60°sector on the rotating arena. Afterwards, sector was relocated to the opposite side of the rotating arena (reversal). The administration of temozolomide significantly improved the reversal performance compared to saline-treated rats. Our results suggest a significant, level-dependent, improvement of reversal learning in animals with reduced adult neurogenesis in hippocampus.
Muscarinic acetylcholine receptors (mAChRs) have been found to regulate many diverse functions, r... more Muscarinic acetylcholine receptors (mAChRs) have been found to regulate many diverse functions, ranging from motivation and feeding to spatial navigation, an important and widely studied type of cognitive behavior. Systemic administration of non-selective antagonists of mAChRs, such as scopolamine or atropine, have been found to have adverse effects on a vast majority of place navigation tasks. However, many of these results may be potentially confounded by disruptions of functions other than spatial learning and memory. Although studies with selective antimuscarinics point to mutually opposite effects of M1 and M2 receptors, their particular contribution to spatial cogni-tion is still poorly understood, partly due to a lack of truly selective agents. Furthermore, constitutive knockouts do not always support results from selective antagonists. For modeling impaired spatial cognition, the scopolamine-induced amnesia model still maintains some limited validity, but there is an apparent need for more targeted approaches such as local intracerebral administration of antagonists, as well as novel techniques such as optogenetics focused on cholinergic neurons and chemogenetics aimed at cells expressing metabotropic mAChRs.
The hippocampus and retrosplenial cortex are integrated within a higher-order cognitive circuit s... more The hippocampus and retrosplenial cortex are integrated within a higher-order cognitive circuit supporting relational (spatial, contextual, episodic) forms of learning and memory. Hippocampal place cells can coordinate multiple parallel representations in the same physical environment. Novel environment exploration triggers expression of immediate-early genes (IEGs) Arc and Homer1a in spatial context-specific ensembles of CA1 and CA3 neurons. Less is know about ensemble coding in the retrosplenial cortex (RSC), a region directly connected and functionally coupled to CA1. Hippocampal and retrosplenial damage is found in patients with schizophrenia alongside cognitive deficits affecting relational memory. Systemic administration of non-competitive NMDAR antagonists such as MK-801 is used to model psychosis in animals and humans. Acute systemic MK-801 (0.15 mg/kg) impaired cogni-tive control in rats and ensemble code for spatial context in CA1. Here, we use expression of immediate-early genes Arc and Homer 1a to examine ensemble coding in rat CA3 and RSC to test if the effect of MK-801 extends upstream and downstream of CA1, respectively. Different rats explored the same context twice (A/A), explored two distinct contexts (A/B) or remained in their home cage (CC). In contrast to CA1, MK-801 did not affect ensemble coding in CA3. Unlike CA3 and CA1, similarity of RSC ensembles active during exploration did not reflect change in spatial context, but MK-801 (0.15 mg/kg) increased similarity in RSC ensembles active during spontaneous behavior in the home cage. The data provide support for MK-801-induced functional uncoupling between CA3 and CA1 and suggest that ensemble coding deficit may extend downstream of CA1. This deficit may reflect hyper-associative state in the cognitive circuit underlying cognitive disorgani-zation in psychosis. V
Although animals often learn and monitor the spatial properties of relevant moving objects such a... more Although animals often learn and monitor the spatial properties of relevant moving objects such as con-specifics and predators to properly organize their own spatial behavior, the underlying brain substrate has received little attention and hence remains elusive. Because the anterior cingulate cortex (ACC) participates in conflict monitoring and effort-based decision making, and ACC neurons respond to objects in the environment, it may also play a role in the monitoring of moving cues and exerting the appropriate spatial response. We used a robot avoidance task in which a rat had to maintain at least a 25 cm distance from a small programmable robot to avoid a foot shock. In successive sessions, we trained ten Long Evans male rats to avoid a fast-moving robot (4 cm/s), a stationary robot, and a slow-moving robot (1 cm/s). In each condition, the ACC was transiently inactivated by bilateral injections of muscimol in the penultimate session and a control saline injection was given in the last session. Compared to the corresponding saline session, ACC-inactivated rats received more shocks when tested in the fast-moving condition, but not in the stationary or slow robot conditions. Furthermore, ACC-inactivated rats less frequently responded to an approaching robot with appropriate escape responses although their response to shock stimuli remained preserved. Since we observed no effect on slow or stationary robot avoidance, we conclude that the ACC may exert cognitive efforts for monitoring dynamic updating of the position of an object, a role complementary to the dorsal hippocampus.
The mechanism of tacrine as a precognitive drug has been considered to be complex and not fully u... more The mechanism of tacrine as a precognitive drug has been considered to be complex and not fully understood. It has been reported to involve a wide spectrum of targets involving cholinergic, gabaergic, nitrinergic and gluta-matergic pathways. Here, we review the effect of tacrine and its derivatives on the NMDA receptors (NMDAR) with a focus on the mechanism of action and biological consequences related to the Alzheimer's disease treatment. Our findings indicate that effect of tacrine on glutamatergic neurons is both direct and indirect. Direct NMDAR antagonistic effect is often reported by in vitro studies; however, it is achieved by high tacrine concentrations which are not likely to occur under clinical conditions. The impact on memory and behavioral testing can be ascribed to indirect effects of tacrine caused by influencing the NMDAR-mediated currents via M1 receptor activation , which leads to inhibition of Ca 2+-activated potassium channels. Such inhibition prevents membrane re-polarization leading to prolonged NMDAR activation and subsequently to long term potentiation. Considering these findings, we can conclude that tacrine-derivatives with dual cholinesterase and NMDARs modulating activity may represent a promising approach in the drug development for diseases associated with cognitive dysfunc-tion, such as the Alzheimer disease.
The function of adult neurogenesis in the dentate gyrus is not yet completely understood, though ... more The function of adult neurogenesis in the dentate gyrus is not yet completely understood, though many competing theories have attempted to explain the function of these newly-generated neurons. Most theories give adult neurogenesis a role in aiding known hippocampal/dentate gyrus functions. Other theories offer a novel role for these new cells based on their unique physiological qualities, such as their low excitability threshold. Many behavioral tests have been used to test these theories, but results have been inconsistent and often contradictory. Substantial variability in tests and protocols may be at least partially responsible for the mixed results. On the other hand, conflicting results arising from the same tests can serve as aids in elucidating the function of adult neurogenesis. Here, we offer a hypothesis that considers the cognitive nature of tasks commonly used to assess the function of adult neurogenesis, and introduce a dichotomy between tasks focused on discrimination vs. generalization. We view these two aspects as opposite ends of the continuous spectrum onto which traditional tests can be mapped. We propose that high neurogenesis favors behavioral discrimination while low adult neurogenesis favors behavioral generalization of a knowledge or rule. Since many tasks require both, the effects of neurogenesis could be cancelled out in many cases. Although speculative, we hope that our view presents an interesting and testable hypothesis of the effect of adult neurogenesis in traditional behavioral tasks. We conclude that new, carefully designed behavioral tests may be necessary to reach a final consensus on the role of adult neurogenesis in behavior.
Adult neurogenesis in the dentate gyrus adds a substantial number of new functional neurons to th... more Adult neurogenesis in the dentate gyrus adds a substantial number of new functional neurons to the hip-pocampus network in rodents. To date, however, the function of these new granule cells remains unclear. We conducted an experiment to assess the contribution of adult neurogenesis in the dentate gyrus to acquisition and reversal learning in a task that predominantly requires generalization of a rule. Young adult male Long-Evans rats were repeatedly administered either a cytostatic temozolomide or saline for a period of four weeks (3 injections per week). Post treatment, animals were injected with bromod-eoxyuridine to quantify adult neurogenesis in the dentate gyrus. For behavioral assessment we used hippocampus-dependent active place avoidance with reversal in a Carousel maze. Animals first learned to avoid a 60° sector on the rotating arena. Afterwards, sector was relocated to the opposite side of the rotating arena (reversal). The administration of temozolomide significantly improved the reversal performance compared to saline-treated rats. Our results suggest a significant, level-dependent, improvement of reversal learning in animals with reduced adult neurogenesis in hippocampus.
Rationale Development of new drugs for treatment of Alzheimer's disease (AD) requires valid parad... more Rationale Development of new drugs for treatment of Alzheimer's disease (AD) requires valid paradigms for testing their efficacy and sensitive tests validated in translational research. Objectives We present validation of a place-navigation task, a Hidden Goal Task (HGT) based on the Morris water maze (MWM), in comparable animal and human protocols. Methods We used scopolamine to model cognitive dysfunc-tion similar to that seen in AD and donepezil, a symptomatic medication for AD, to assess its potential reversible effect on this scopolamine-induced cognitive dysfunction. We tested the effects of scopolamine and the combination of scopol-amine and donepezil on place navigation and compared their effects in human and rat versions of the HGT. Place navigation testing consisted of 4 sessions of HGT performed at baseline, 2, 4, and 8 h after dosing in humans or 1, 2.5, and 5 h in rats. Results Scopolamine worsened performance in both animals and humans. In the animal experiment, co-administration of donepezil alleviated the negative effect of scopolamine. In the human experiment, subjects co-administered with scopol-amine and donepezil performed similarly to subjects on placebo and scopolamine, indicating a partial ameliorative effect of donepezil. Conclusions In the task based on the MWM, scopolamine impaired place navigation, while co-administration of donepezil alleviated this effect in comparable animal and human protocols. Using scopolamine and donepezil to challenge place navigation testing can be studied concurrently in animals and humans and may be a valid and reliable model for
The aim of the present study was an evaluation of prenatal exposure to acute methamphetamine (MA)... more The aim of the present study was an evaluation of prenatal exposure to acute methamphetamine (MA) treatment on manifestations of anxiety. Anxiety was evaluated in adult animals in three different experimental models: the Elevated plus-maze (EPM), Social interaction test (SIT) and Ultrasound vocalization (USV). Female rats were administered saline (S) or MA (5mg/kg) daily throughout their entire gestation period. The male progeny, in adulthood, were administered with challenge dose of S or MA (1mg/kg) prior to evaluation of anxiety. The study demonstrated that prenatal MA exposure increased the anxiogenic effect on evaluated behaviour patterns in the USV model and to a lesser degree in the EPM model. In addition, the acute MA challenge in adulthood decreased the time spent during social interaction suggesting an anxiogenic effect in the SIT model as well. On the other hand, some of the evaluated parameters (e.g. the number of head-dipping in the EPM and number of dropped boluses in the SIT) also suggest MA-induced anxiolytic effects. Sensitization to a MA challenge was apparent in several parameters of the EPM (e.g. increased number of entries to the closed arms, increased stretched attend postures and increased approach-avoid conflicts) and SIT (total social interaction and following). The present data demonstrate that prenatal MA exposure and adult challenge of the same drug have diverse effects on animal behaviour that depends on the type of anxiety model used.
On the Carousel maze, rats are trained to avoid a sector of a circular rotating arena, punishable... more On the Carousel maze, rats are trained to avoid a sector of a circular rotating arena, punishable by a mild electric foot-shock. In the room frame (RF) variant, the punishable sector remains stable relative to the room, while in the arena frame (AF) version, the sector rotates with the arena. The rats therefore need to disregard local olfactory, tactile and self-motion cues in RF condition and distal extra-maze landmarks in the AF task. In both primates and rodents, the coordination of various spatial reference frames is thought to depend on the posterior parietal cortex (PPC). We have previously shown that PPC-lesioned rats can solve both variants of the Carousel avoidance task. Here we aimed to determine the effects of bilateral thermocoagulation lesion of the PPC in Long-Evans rats on the ability to transition between multiple spatial strategies. The rats were first trained in five sessions in one condition and then another five sessions in the other. The following training schem...
A number of studies demonstrated a rapid onset of an antidepressant effect of non-competitive N-m... more A number of studies demonstrated a rapid onset of an antidepressant effect of non-competitive N-methyl-d-aspartic acid receptor (NMDAR) antagonists. Nonetheless, its therapeutic potential is rather limited, due to a high coincidence of negative side-effects. Therefore, the challenge seems to be in the development of NMDAR antagonists displaying antidepressant properties, and at the same time maintaining regular physiological function of the NMDAR. Previous results demonstrated that naturally occurring neurosteroid 3α5β-pregnanolone sulfate shows pronounced inhibitory action by a use-dependent mechanism on the tonically active NMDAR. The aim of the present experiments is to find out whether the treatment with pregnanolone 3αC derivatives affects behavioral response to chronic and acute stress in an animal model of depression. Adult male mice were used throughout the study. Repeated social defeat and forced swimming tests were used as animal models of depression. The effect of the dru...
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Papers and abstracts by Ales Stuchlik