Experience-dependent effects of muscimol-induced hippocampal excitation on mnemonic discrimination

Johnson, Sarah A.; Turner, Sean M.; Lubke, Katelyn N.; Cooper, Tara L.; Fertal, Kaeli E.; Bizon, Jennifer L.; Maurer, Andrew P.; Burke, Sara N.

doi:10.1101/454744

Cited by 3 publications

(25 citation statements)

References 98 publications

(133 reference statements)

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“…Prefrontal muscimol infusions impaired mnemonic discrimination of a target object from both distinct and similar lure objects, with the effect most pronounced for similar lures. Further, in contrast to effects of hippocampal muscimol infusions (Johnson et al, 2018), disrupting prefrontal activity impaired performance irrespective of prior task experience.…”

Section: Introductionmentioning

confidence: 70%

“…Procedures for habituation and procedural training were similar to those previously described (Johnson et al, 2017(Johnson et al, , 2018. Rats were habituated to eating small pieces of Froot Loop cereal (Kellogg's; Battle Creek, MI) or marshmallows (Medley Hills Farm, Medina, OH), which served as food rewards throughout experiments, by providing pieces with daily chow for 1-3 days.…”

Section: Habituation and Procedural Trainingmentioning

confidence: 99%

“…While disrupting activity within CA3/DG impaired discrimination performance in young adults, this effect was contingent on prior task experience. Specifically, infusions of the GABA A agonist muscimol in CA3/DG impaired discrimination in a first block of tests when lure objects were novel, but not on subsequent second and third blocks of tests as lures became familiar (Johnson et al, 2018). In contrast, interference with perforant path input to the hippocampus impaired mnemonic discrimination performance across multiple tests (Burke et al, 2018b).…”

Section: Introductionmentioning

confidence: 98%

“…Given CA3/DG activity has been consistently linked to mnemonic discrimination performance in both young and older adults (Kirwan and Stark, 2007;Bakker et al, 2008;Lacy et al, 2011;Yassa et al, 2011a;Motley and Kirwan, 2012;Doxey and Kirwan, 2015; 2018), we recently tested the requirement of intact neural activity in these hippocampal regions for distinguishing similar objects in rats (Johnson et al, 2018). While disrupting activity within CA3/DG impaired discrimination performance in young adults, this effect was contingent on prior task experience.…”

Section: Introductionmentioning

confidence: 99%

“…The current study investigated how prefrontal cortical activity contributes to the discrimination of similar objects in a rodent mnemonic similarity task (Johnson et al, 2017(Johnson et al, , 2018. Rats were trained on task procedures, then implanted with guide cannulae targeting prelimbic and infralimbic regions of the medial prefrontal cortex.…”

Section: Introductionmentioning

confidence: 99%

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Rodent mnemonic similarity task performance requires the prefrontal cortex

Johnson

Zequeira

Turner

et al. 2020

Preprint

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Mnemonic similarity task performance, in which a known target stimulus must be distinguished from similar lures, is supported by the hippocampus and perirhinal cortex and is known to decline in advanced age. Interestingly, disrupting hippocampal activity leads to mnemonic discrimination impairments when lures are novel, but not when they are familiar. This observation suggests other brain structures can support discrimination abilities as stimuli are learned. The prefrontal cortex (PFC) is critical for retrieval of remote events and executive functions, such as working memory, and is also particularly vulnerable to dysfunction in aging. Importantly, the medial PFC is reciprocally connected to the perirhinal cortex and neuron firing in this region coordinates communication between lateral entorhinal and perirhinal cortices to presumably modulate hippocampal activity. This anatomical organization and function of the medial PFC suggests that it contributes to mnemonic discrimination; however, this notion has not been empirically tested. In the current study, young adult male and female F344 x Brown Norway F1 hybrid rats were trained on a rodent object-based mnemonic similarity task, and surgically implanted with guide cannulae targeting prelimbic and infralimbic regions of the medial PFC. Prior to mnemonic discrimination tests, rats received PFC infusions of the GABAA agonist muscimol. Analyses of expression of the neuronal activity-dependent immediate-early gene Arc in medial PFC and adjacent cortical regions confirmed muscimol infusions led to neuronal inactivation in the infralimbic and prelimbic cortices. Moreover, muscimol infusions in PFC impaired mnemonic discrimination performance relative to the vehicle control across all testing blocks when lures shared 50-90% feature overlap with the target. Thus, in contrast to prior results from rats given hippocampal muscimol infusions, PFC inactivation impaired target-lure discrimination regardless of the novelty or familiarity of the lures. These findings indicate the PFC plays a critical role in mnemonic similarity task performance, but the time course of PFC involvement is dissociable from that of the hippocampus.

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Section: Introductionmentioning

confidence: 70%

Section: Habituation and Procedural Trainingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Rodent mnemonic similarity task performance requires the prefrontal cortex

Johnson

Zequeira

Turner

et al. 2020

Preprint

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Behavioral pattern separation and cognitive flexibility are enhanced in a mouse model of increased lateral entorhinal cortex-dentate gyrus circuit activity

Yun

Soler

Tran

et al. 2023

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Behavioral pattern separation and cognitive flexibility are essential cognitive abilities which are disrupted in many brain disorders. Better understanding of the neural circuitry involved in these abilities will open paths to treatment. In humans and mice, discrimination and adaptation rely on integrity of the hippocampal dentate gyrus (DG) which both receive glutamatergic input from the entorhinal cortex (EC), including the lateral EC (LEC). Inducible increase of EC-DG circuit activity improves simple hippocampal-dependent associative learning and increases DG neurogenesis. Here we asked if the activity of LEC fan cells that directly project to the DG (LEC→DG neurons) regulates behavioral pattern separation or cognitive flexibility. C57BL6/J male mice received bilateral LEC infusions of a virus expressing shRNA TRIP8b, an auxiliary protein of an HCN channel or a control virus (SCR shRNA); this approach increases the activity of LEC→DG neurons. Four weeks later, mice underwent testing for behavioral pattern separation and reversal learning (touchscreen-based Location Discrimination Reversal [LDR] task) and innate fear of open spaces (elevated plus maze [EPM]) followed by counting of new DG neurons (doublecortin-immunoreactive cells [DCX+] cells). TRIP8b and SCR shRNA mice performed similarly in general touchscreen training and LDR training. However, in late LDR testing, TRIP8b shRNA mice reached the first reversal more quickly and had more accurate discrimination vs. SCR shRNA mice, specifically when pattern separation was challenging (lit squares close together or small separation). Also, TRIP8b shRNA mice achieved more reversals in late LDR testing vs. SCR shRNA mice. Supporting a specific influence on cognitive behavior, SCR shRNA and TRIP8b shRNA mice did not differ in total distance traveled or in time spent in the closed arms of the EPM. Supporting an inducible increase in LEC-DG activity, DG neurogenesis was increased. These data indicate TRIP8b shRNA mice had better pattern separation and reversal learning and more neurogenesis vs. SCR shRNA mice. This work advances fundamental and translational neuroscience knowledge relevant to two cognitive functions critical for adaptation and survival —behavioral pattern separation and cognitive flexibility — and suggests the activity of LEC→DG neurons merits exploration as a therapeutic target to normalize dysfunctional DG behavioral output.

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Perforant Path Fiber Loss Results in Mnemonic Discrimination Task Deficits in Young Rats

Burke

Turner

Desrosiers

et al. 2018

Front. Syst. Neurosci.

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The observation that entorhinal input to the hippocampus declines in old age is well established across human studies and in animal models. This loss of perforant path fibers is exaggerated in individuals with episodic memory deficits and Mild Cognitive Impairment, suggesting that perforant path integrity is associated with progression to Alzheimer’s Disease. During normal aging, behaviors that measure the ability of a study participant to discriminate between stimuli that share features is particularly sensitive to perforant fiber loss. Evidence linking perforant path changes to cognitive decline, however, has been largely correlational. Thus, the current study tested the causative role of perforant path fiber loss in behavioral decline by performing a unilateral knife cut to disconnect the entorhinal cortex from the hippocampus in the right hemisphere in young male and female rats. This approach does not completely disconnect the hippocampus from the entorhinal cortex but rather reduces the effective connectivity between these two structures. Male and female rats were then tested on the rodent variant of the mnemonic discrimination task, which is believed to critically rely on perforant path fiber integrity. Right hemisphere perforant path transections produced a significant impairment in the abilities of lesioned animals to discriminate between objects with high levels of feature overlap. This deficit was not observed in the male and female sham groups that received a cut to cortex above the white matter. Together these data support the view that, across species, age-related perforant path fiber loss produces behavioral deficits in the ability to discriminate between stimuli with perceptual overlap.

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Experience-dependent effects of muscimol-induced hippocampal excitation on mnemonic discrimination

Abstract: for their help with carrying out behavioral experiments and analyses of video recordings. We also thank Abbi Hernandez for assistance in collecting tissue for histology.

Cited by 3 publications

References 98 publications

Rodent mnemonic similarity task performance requires the prefrontal cortex

Rodent mnemonic similarity task performance requires the prefrontal cortex

Behavioral pattern separation and cognitive flexibility are enhanced in a mouse model of increased lateral entorhinal cortex-dentate gyrus circuit activity

Perforant Path Fiber Loss Results in Mnemonic Discrimination Task Deficits in Young Rats

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