High-affinity choline transport (HAChT) is the rate limiting step in the synthesis of acetylcholi... more High-affinity choline transport (HAChT) is the rate limiting step in the synthesis of acetylcholine (ACh). The activity of HAChT and the binding of its selective inhibitor, [3H]hemicholinium-3 (HC-3) are affected by a number of exogenous and endogenous factors. Previous experiments demonstrated that Vitamin E pretreatment could prevent the decrease in HAChT and the cognitive deficits induced by the cholinotoxin AF64A [38]. To further examine this effect these experiments determined whether Vitamin E would alter the efficacy of both irreversible (AF64A) and reversible (HC-3) inhibitors of HAChT. In Experiment 1, rats were pretreated with Vitamin E (50 mg/kg), 24 h and 15 min, prior to bilateral icv injection of AF64A (0, 0.75, 1.5, or 3.0 nmol). HAChT was assessed in hippocampal synaptosomes, 14 days following surgery. Vitamin E prevented the dose-dependent AF64A-induced inhibition of HAChT in the hippocampus (HPC). In a second experiment, rats were pretreated with Vitamin E as above, and infused (icv) with the reversible inhibitor of HAChT, HC-3 (20 μg), or CSF. HAChT in the HPC was assessed 30 min, 4, 12, or 24 h after injection. HC-3 produced a significant decrease of HAChT (58%) that was maximal at 4 h and recovered by 24 h. Vitamin E significantly attenuated, but did not prevent, the inhibition of HAChT produced by HC-3. These experiments demonstrate that Vitamin E pretreatment can attenuate the effects of both reversible and irreversible inhibitors of HAChT. These data are discussed in terms of potential underlying mechanisms. It is possible that the neuroprotectant effects of Vitamin E on both reversible and irreversible inhibitors of HAChT reflect an action at the choline carrier and not an antioxidant effect.
Mapping of the brainstem regions sensitive to beta-endorphin and morphine for antinociception and... more Mapping of the brainstem regions sensitive to beta-endorphin and morphine for antinociception and Met-enkephalin release was performed in rats. Antinociception was assessed by the tail-flick test in pentobarbital-anesthetized rats and the release of immunoreactive Met-enkephalin from the spinal cord was measured by lumbar-cisternal perfusion in urethane-anesthetized rats. The sites in the brainstem most sensitive to beta-endorphin (2 micrograms) for inhibition of the tail-flick response and Met-enkephalin release were located in areas in the caudal medial medulla such as raphe obsacurus nucleus and raphe pallidus nucleus and the adjacent midline reticular formation. Sites in the rostral medial medulla were less sensitive to beta-endorphin for both antinociception and release of Met-enkephalin. The regions 1 mm and more lateral to the midline were not sensitive to beta-endorphin. The sites sensitive to morphine sulfate (4 micrograms) for antinociception were located in areas in the rostral ventromedial medulla such as raphe magnus nucleus, gigantocellular reticular nucleus and gigantocellular reticular nucleus alpha. Raphe obscurus nucleus, which was sensitive to beta-endorphin, was not sensitive to morphine for antinociception. Locus coeruleus was sensitive to morphine and beta-endorphin for antinociception. No sites sensitive to morphine were found for Met-enkephalin release. The correlation between the brainstem sites sensitive to beta-endorphin for the production of antinociception and the release of Met-enkephalin suggests that the antinociception induced by beta-endorphin is mediated by the release of Met-enkephalin. The findings of different brainstem sites sensitive to beta-endorphin and morphine support the hypothesis of different modes of pharmacological actions for beta-endorphin and morphine.
Background: Neurodevelopmental disorders are associated with altered patterns of neuronal connect... more Background: Neurodevelopmental disorders are associated with altered patterns of neuronal connectivity. A critical determinant of neuronal connectivity is the dendritic morphology of individual neurons, which is shaped by experience. The identification of environmental exposures that interfere with dendritic growth and plasticity may, therefore, provide insight into environmental risk factors for neurodevelopmental disorders. oBjective: We tested the hypothesis that polychlorinated biphenyls (PCBs) alter dendritic growth and/or plasticity by promoting the activity of ryanodine receptors (RyRs). Methods and results: The Morris water maze was used to induce experience-dependent neural plasticity in weanling rats exposed to either vehicle or Aroclor 1254 (A1254) in the maternal diet throughout gestation and lactation. Developmental A1254 exposure promoted dendritic growth in cerebellar Purkinje cells and neocortical pyramidal neurons among untrained animals but attenuated or reversed experience-dependent dendritic growth among maze-trained littermates. These structural changes coincided with subtle deficits in spatial learning and memory, increased [ 3 H]-ryanodine binding sites and RyR expression in the cerebellum of untrained animals, and inhibition of training-induced RyR upregulation. A congener with potent RyR activity, PCB95, but not a congener with negligible RyR activity, PCB66, promoted dendritic growth in primary cortical neuron cultures and this effect was blocked by pharmacologic antagonism of RyR activity. conclusions: Developmental exposure to PCBs interferes with normal patterns of dendritic growth and plasticity, and these effects may be linked to changes in RyR expression and function. These findings identify PCBs as candidate environmental risk factors for neurodevelopmental disorders, especially in children with heritable deficits in calcium signaling.
The hippocampal formation is essential for forming declarative representations of the relationshi... more The hippocampal formation is essential for forming declarative representations of the relationships among multiple stimuli. The rodent hippocampal formation, including the entorhinal cortex and subicular complex, is critical for spatial memory. Two classes of hippocampal neurons fire in relation to spatial features. Place cells collectively map spatial locations, with each cell firing only when the animal occupies that cell's "place field," a particular subregion of the larger environment. Head direction (HD) cells encode directional heading, with each HD cell firing when the rat's head is oriented in that cell's particular "preferred firing direction." Both landmarks and internal cues (e.g., vestibular, motor efference copy) influence place and HD cell activity. However, as is the case for navigation, landmarks are believed to exert greater influence over place and HD cell activity. Here we show that temporary inactivation of the vestibular system led to the disruption of location-specific firing in hippocampal place cells and direction-specific discharge of postsubicular HD cells, without altering motor function. Place and HD cell activity recovered over a time course similar to that of the restoration of vestibular function. These results indicate that vestibular signals provide an important influence over the expression of hippocampal spatial representations, and may explain the navigational deficits of humans with vestibular dysfunction.
Song et al. SK2 Channels Modulate Visceral Hypersensitivity-Visceral hypersensitivity rats presen... more Song et al. SK2 Channels Modulate Visceral Hypersensitivity-Visceral hypersensitivity rats presented an increase in neuronal firing rate in the spinal dorsal horn.-Intrathecal administration of SK2 channel activator 1-EBIO or CyPPA prevented visceral hypersensitivity and decrease in I AHP .
Medial and lateral entorhinal cortices convey spatial/contextual and item/object information to t... more Medial and lateral entorhinal cortices convey spatial/contextual and item/object information to the hippocampus, respectively. Whether the distinct inputs are integrated as one cognitive map by hippocampal neurons to represent location and the objects therein, or whether they remain as parallel outputs, to be integrated in a downstream region, remains unclear. Principal, or complex spike bursting, neurons of hippocampus exhibit location-specific firing, and it is likely that the activity of “place cells” supports spatial memory/navigation in rodents. Consistent with cognitive map theory, the activity of CA1 hippocampal neurons is also critical for nonspatial memory, such as object recognition. However, the degree to which CA1 neuronal activity represents the associations of object-context or object-in-place memory is not well understood. Here, the contributions of mouse CA1 neuronal activity to object recognition memory and the emergence of object-place conjunctive representations w...
Recognition of a previously experienced item or object depends upon the successful retrieval of m... more Recognition of a previously experienced item or object depends upon the successful retrieval of memory for the object. The neural mechanisms that support object recognition memory in the mammalian brain are not well understood. The rodent hippocampus plays a well-established role in spatial memory, and we previously demonstrated that temporary inactivation of the mouse hippocampus impairs object memory, as assessed with a novel object preference (NOP) test. The present studies were designed to test some remaining issues regarding the contribution of the CA1 sub-region of the mouse dorsal hippocampus to long-term object memory. Specifically, we examined whether the retrieval of spatial memory (as assessed by the Morris water maze; MWM) and object recognition memory are differentially sensitive to inactivation of the CA1 region. The current study used pre-test local microinfusion of muscimol directly into the CA1 region of dorsal hippocampus to temporarily interrupt its function durin...
A central question in the field of aging research is to identify the cellular and molecular basis... more A central question in the field of aging research is to identify the cellular and molecular basis of neuroresilience. One potential candidate is the small GTPase, Rab10. Here, we used Rab10+/−mice to investigate the molecular mechanisms underlying Rab10-mediated neuroresilience. Brain expression analysis of 880 genes involved in neurodegeneration showed that Rab10+/−mice have increased activation of pathways associated with neuronal metabolism, structural integrity, neurotransmission, and neuroplasticity compared with their Rab10+/+littermates. Lower activation was observed for pathways involved in neuroinflammation and aging. We identified and validated several differentially expressed genes (DEGs), including Stx2, Stx1b, Vegfa, and Lrrc25 (downregulated) and Prkaa2, Syt4, and Grin2d (upregulated). Behavioral testing showed that Rab10+/−mice perform better in a hippocampal-dependent spatial task (object in place test), while their performance in a classical conditioning task (trace...
Supplemental Figure to Asgeirsdottir et al. manuscript entitled, "Object and place informati... more Supplemental Figure to Asgeirsdottir et al. manuscript entitled, "Object and place information processing by CA1 hippocampal neurons of C57BL/6J mice" under review at Journal of Neurophysiology.<br> Suppl. Figure 1. Hippocampal CA1 object-related firing. <b>a)</b> Representative placement of the unilateral tetrode arrays implanted over the CA1 region of the right and medial dorsal hippocampus for four mice (blue-filled circles) that object cell activity was recorded from. <b>b)</b> Representative place x firing rate maps from a CA1 place cell and a simultaneously recorded CA1 object cell during habituation 2 and test of the OR task (note difference in Hz scale). The firing rate is represented by the color-coded pixels, with red referring to the location(s) where the cell discharged at its highest rate, and blue referring to the visited locations where the cell was silent. White pixels represent areas of the arena that were unvisited by the mou...
Supplemental Figure to Asgeirsdottir et al. manuscript entitled, "Object and place informati... more Supplemental Figure to Asgeirsdottir et al. manuscript entitled, "Object and place information processing by CA1 hippocampal neurons of C57BL/6J mice" under review at Journal of Neurophysiology.<br> Suppl. Figure 1. Hippocampal CA1 object-related firing. <b>a)</b> Representative placement of the unilateral tetrode arrays implanted over the CA1 region of the right and medial dorsal hippocampus for four mice (blue-filled circles) that object cell activity was recorded from. <b>b)</b> Representative place x firing rate maps from a CA1 place cell and a simultaneously recorded CA1 object cell during habituation 2 and test of the OR task (note difference in Hz scale). The firing rate is represented by the color-coded pixels, with red referring to the location(s) where the cell discharged at its highest rate, and blue referring to the visited locations where the cell was silent. White pixels represent areas of the arena that were unvisited by the mou...
The increasing prescription of opioids is fueling an epidemic of addiction and overdose deaths. M... more The increasing prescription of opioids is fueling an epidemic of addiction and overdose deaths. Morphine is a highly addictive drug characterized by a high relapse rate - even after a long period of abstinence. Serotonin (5-HT) neurotransmission participates in the development of morphine dependence, as well as the expression of morphine withdrawal. In this study, we examined the effect of blockade of 5-HT2A receptors (5-HT2ARs) on morphine-induced behavioral sensitization and withdrawal in male mice. 5-HT2AR antagonist MDL 11,939 (0.5 mg/kg, i.p.) suppressed acute morphine (5.0 mg/kg, s.c.)-induced increase in locomotor activity. Mice received morphine (10 mg/kg, s.c.) twice a day for 3 days and then drug treatment was suspended for 5 days. On day 9, a challenge dose of morphine (10 mg/kg) was administered to induce the expression of behavioral sensitization. MDL 11,939 (0.5 mg/kg, i.p.) pretreatment suppressed the expression of morphine-induced behavioral sensitization. Another co...
Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, 2017
Background-Despite our understanding of the significance of the prefrontal cortex in the consolid... more Background-Despite our understanding of the significance of the prefrontal cortex in the consolidation of long-term memories (LTM), its role in the encoding of LTM remains elusive. Here we investigated the role of new protein synthesis in the mouse medial prefrontal cortex (mPFC) in encoding contextual fear memory. Methods-Because a change in the association of mRNAs to polyribosomes is an indicator of new protein synthesis, we assessed the changes in polyribosome-associated mRNAs in the mPFC following contextual fear conditioning (CFC) in the mouse. Differential gene expression in mPFC was identified by polyribosome profiling (n = 18). The role of new protein synthesis in mPFC was determined by focal inhibition of protein synthesis (n = 131) and by intra-prelimbic cortex manipulation (n = 56) of Homer 3, a candidate identified from polyribosome profiling. Results-We identified several mRNAs that are differentially and temporally recruited to polyribosomes in the mPFC following CFC. Inhibition of protein synthesis in the prelimbic (PL), but not in the anterior cingulate cortex (ACC) region of the mPFC immediately after CFC disrupted encoding of contextual fear memory. Intriguingly, inhibition of new protein synthesis in the PL 6 hours after CFC did not impair encoding. Furthermore, expression of Homer 3, an mRNA *
ABSTRACT The purpose of this chapter is to provide an overview of a current approach in defining ... more ABSTRACT The purpose of this chapter is to provide an overview of a current approach in defining the relationships between the firing patterns of groups of neurons recorded from the freely behaving rodent. The design and construction of a 16-channel headstage and its typical integration with a commercially available multichannel data acquisition system is described in detail. Next, the chapter examines the strategies necessary to test the behavioral significance of firing patterns of individual neurons recorded from behaving animals. A discussion is included that surveys the limitations and advantages inherent in testing how discrete behavioral events are represented in single-unit activity recorded from rodents engaged in spatial and nonspatial behaviors. To expand on the technological and theoretical approaches to establishing the relationship between single-unit activity and behavior, the rodent head direction cell system is described as one useful model system. The head direction cell is considered by many to represent the directional sense of the organism and to be essential for spatial navigation. The chapter provides a critical overview of the studies that have been conducted to date to test this relationship. In short, these are the record while the rodent performs some navigational task experiments. Examination of the results from the studies reveals that there is little clear evidence to support the view that head direction cells guide spatial navigation. The ensuing discussion addresses putative reasons for the division between the empirical data and the theory of head direction cell – behavior relations. The chapter concludes with clear suggestions for alternative experimental approaches that might better address brain–behavior relationships. A plea for increased open dialogue between the fields of behavioral analysis and systems/cellular neurophysiology emerges. Improved understanding of the contributions to the neuroscience field made by behavioral neuroscientists and those by electrophysiologists should raise the bar of modern approaches to brain–behavioral relationship studies using in vivo electrophysiological methods.
Neurotransmitter Interactions and Cognitive Function, 1992
Memory is one of the most enduring challenges in all of behavioral neuroscience. A memory “system... more Memory is one of the most enduring challenges in all of behavioral neuroscience. A memory “system” must be able to engage a diverse array of neural systems that serve perceptual, emotive, and cognitive functions. It needs to (a) access and process sensory information, (b) analyze its biological significance in a specific context, determine (c) whether, (d) how, and (e) where that information should be stored, and (f) the appropriate context in which to later use it. To appreciate the rich complexity of the process we need to examine the interplay of systems that support memory and not just focus on a single brain structure or neurotransmitter. The remnants of memory reside in circuits not synapses. To understand the drama of memory we need to listen to the dialogue of all of the characters.
Rats were trained on a radial maze and then given electrolytic lesions of the MS followed by a si... more Rats were trained on a radial maze and then given electrolytic lesions of the MS followed by a single intraseptal injection of 5 /zg of NGF. Three days later they were re-tested on the maze. They were also post-operatively tested for hyperemotionality. MS lesions severely impaired performance on the radial maze and produced increased emotionality. MS lesions also produced a general decrease in hippocampal high affinity choline transport and acetylcholinesterase staining, which was not affected by NGF administration. NGF treatment ameliorated the behavioral deficit in the radial maze but had no effect on the hyperemotionality. In order to determine whether the NGF was working to restore previously learned spatial abilities, the type of learning strategy used by the animals was also assessed. NGF treatment did not restore previously learned spatial strategies but facilitated recovery of alternative learning strategies. The reduction in cognitive deficit was also paralleled by reduced ventricular enlargement in the NGF treated rats. The present results suggest that a single injection of NGF can produce a long-lasting improvement on a cognitive task and reduce some of the injury-induced, secondary reactive changes that occur following electrolytic MS lesions.
High-affinity choline transport (HAChT) is the rate limiting step in the synthesis of acetylcholi... more High-affinity choline transport (HAChT) is the rate limiting step in the synthesis of acetylcholine (ACh). The activity of HAChT and the binding of its selective inhibitor, [3H]hemicholinium-3 (HC-3) are affected by a number of exogenous and endogenous factors. Previous experiments demonstrated that Vitamin E pretreatment could prevent the decrease in HAChT and the cognitive deficits induced by the cholinotoxin AF64A [38]. To further examine this effect these experiments determined whether Vitamin E would alter the efficacy of both irreversible (AF64A) and reversible (HC-3) inhibitors of HAChT. In Experiment 1, rats were pretreated with Vitamin E (50 mg/kg), 24 h and 15 min, prior to bilateral icv injection of AF64A (0, 0.75, 1.5, or 3.0 nmol). HAChT was assessed in hippocampal synaptosomes, 14 days following surgery. Vitamin E prevented the dose-dependent AF64A-induced inhibition of HAChT in the hippocampus (HPC). In a second experiment, rats were pretreated with Vitamin E as above, and infused (icv) with the reversible inhibitor of HAChT, HC-3 (20 μg), or CSF. HAChT in the HPC was assessed 30 min, 4, 12, or 24 h after injection. HC-3 produced a significant decrease of HAChT (58%) that was maximal at 4 h and recovered by 24 h. Vitamin E significantly attenuated, but did not prevent, the inhibition of HAChT produced by HC-3. These experiments demonstrate that Vitamin E pretreatment can attenuate the effects of both reversible and irreversible inhibitors of HAChT. These data are discussed in terms of potential underlying mechanisms. It is possible that the neuroprotectant effects of Vitamin E on both reversible and irreversible inhibitors of HAChT reflect an action at the choline carrier and not an antioxidant effect.
Mapping of the brainstem regions sensitive to beta-endorphin and morphine for antinociception and... more Mapping of the brainstem regions sensitive to beta-endorphin and morphine for antinociception and Met-enkephalin release was performed in rats. Antinociception was assessed by the tail-flick test in pentobarbital-anesthetized rats and the release of immunoreactive Met-enkephalin from the spinal cord was measured by lumbar-cisternal perfusion in urethane-anesthetized rats. The sites in the brainstem most sensitive to beta-endorphin (2 micrograms) for inhibition of the tail-flick response and Met-enkephalin release were located in areas in the caudal medial medulla such as raphe obsacurus nucleus and raphe pallidus nucleus and the adjacent midline reticular formation. Sites in the rostral medial medulla were less sensitive to beta-endorphin for both antinociception and release of Met-enkephalin. The regions 1 mm and more lateral to the midline were not sensitive to beta-endorphin. The sites sensitive to morphine sulfate (4 micrograms) for antinociception were located in areas in the rostral ventromedial medulla such as raphe magnus nucleus, gigantocellular reticular nucleus and gigantocellular reticular nucleus alpha. Raphe obscurus nucleus, which was sensitive to beta-endorphin, was not sensitive to morphine for antinociception. Locus coeruleus was sensitive to morphine and beta-endorphin for antinociception. No sites sensitive to morphine were found for Met-enkephalin release. The correlation between the brainstem sites sensitive to beta-endorphin for the production of antinociception and the release of Met-enkephalin suggests that the antinociception induced by beta-endorphin is mediated by the release of Met-enkephalin. The findings of different brainstem sites sensitive to beta-endorphin and morphine support the hypothesis of different modes of pharmacological actions for beta-endorphin and morphine.
Background: Neurodevelopmental disorders are associated with altered patterns of neuronal connect... more Background: Neurodevelopmental disorders are associated with altered patterns of neuronal connectivity. A critical determinant of neuronal connectivity is the dendritic morphology of individual neurons, which is shaped by experience. The identification of environmental exposures that interfere with dendritic growth and plasticity may, therefore, provide insight into environmental risk factors for neurodevelopmental disorders. oBjective: We tested the hypothesis that polychlorinated biphenyls (PCBs) alter dendritic growth and/or plasticity by promoting the activity of ryanodine receptors (RyRs). Methods and results: The Morris water maze was used to induce experience-dependent neural plasticity in weanling rats exposed to either vehicle or Aroclor 1254 (A1254) in the maternal diet throughout gestation and lactation. Developmental A1254 exposure promoted dendritic growth in cerebellar Purkinje cells and neocortical pyramidal neurons among untrained animals but attenuated or reversed experience-dependent dendritic growth among maze-trained littermates. These structural changes coincided with subtle deficits in spatial learning and memory, increased [ 3 H]-ryanodine binding sites and RyR expression in the cerebellum of untrained animals, and inhibition of training-induced RyR upregulation. A congener with potent RyR activity, PCB95, but not a congener with negligible RyR activity, PCB66, promoted dendritic growth in primary cortical neuron cultures and this effect was blocked by pharmacologic antagonism of RyR activity. conclusions: Developmental exposure to PCBs interferes with normal patterns of dendritic growth and plasticity, and these effects may be linked to changes in RyR expression and function. These findings identify PCBs as candidate environmental risk factors for neurodevelopmental disorders, especially in children with heritable deficits in calcium signaling.
The hippocampal formation is essential for forming declarative representations of the relationshi... more The hippocampal formation is essential for forming declarative representations of the relationships among multiple stimuli. The rodent hippocampal formation, including the entorhinal cortex and subicular complex, is critical for spatial memory. Two classes of hippocampal neurons fire in relation to spatial features. Place cells collectively map spatial locations, with each cell firing only when the animal occupies that cell's "place field," a particular subregion of the larger environment. Head direction (HD) cells encode directional heading, with each HD cell firing when the rat's head is oriented in that cell's particular "preferred firing direction." Both landmarks and internal cues (e.g., vestibular, motor efference copy) influence place and HD cell activity. However, as is the case for navigation, landmarks are believed to exert greater influence over place and HD cell activity. Here we show that temporary inactivation of the vestibular system led to the disruption of location-specific firing in hippocampal place cells and direction-specific discharge of postsubicular HD cells, without altering motor function. Place and HD cell activity recovered over a time course similar to that of the restoration of vestibular function. These results indicate that vestibular signals provide an important influence over the expression of hippocampal spatial representations, and may explain the navigational deficits of humans with vestibular dysfunction.
Song et al. SK2 Channels Modulate Visceral Hypersensitivity-Visceral hypersensitivity rats presen... more Song et al. SK2 Channels Modulate Visceral Hypersensitivity-Visceral hypersensitivity rats presented an increase in neuronal firing rate in the spinal dorsal horn.-Intrathecal administration of SK2 channel activator 1-EBIO or CyPPA prevented visceral hypersensitivity and decrease in I AHP .
Medial and lateral entorhinal cortices convey spatial/contextual and item/object information to t... more Medial and lateral entorhinal cortices convey spatial/contextual and item/object information to the hippocampus, respectively. Whether the distinct inputs are integrated as one cognitive map by hippocampal neurons to represent location and the objects therein, or whether they remain as parallel outputs, to be integrated in a downstream region, remains unclear. Principal, or complex spike bursting, neurons of hippocampus exhibit location-specific firing, and it is likely that the activity of “place cells” supports spatial memory/navigation in rodents. Consistent with cognitive map theory, the activity of CA1 hippocampal neurons is also critical for nonspatial memory, such as object recognition. However, the degree to which CA1 neuronal activity represents the associations of object-context or object-in-place memory is not well understood. Here, the contributions of mouse CA1 neuronal activity to object recognition memory and the emergence of object-place conjunctive representations w...
Recognition of a previously experienced item or object depends upon the successful retrieval of m... more Recognition of a previously experienced item or object depends upon the successful retrieval of memory for the object. The neural mechanisms that support object recognition memory in the mammalian brain are not well understood. The rodent hippocampus plays a well-established role in spatial memory, and we previously demonstrated that temporary inactivation of the mouse hippocampus impairs object memory, as assessed with a novel object preference (NOP) test. The present studies were designed to test some remaining issues regarding the contribution of the CA1 sub-region of the mouse dorsal hippocampus to long-term object memory. Specifically, we examined whether the retrieval of spatial memory (as assessed by the Morris water maze; MWM) and object recognition memory are differentially sensitive to inactivation of the CA1 region. The current study used pre-test local microinfusion of muscimol directly into the CA1 region of dorsal hippocampus to temporarily interrupt its function durin...
A central question in the field of aging research is to identify the cellular and molecular basis... more A central question in the field of aging research is to identify the cellular and molecular basis of neuroresilience. One potential candidate is the small GTPase, Rab10. Here, we used Rab10+/−mice to investigate the molecular mechanisms underlying Rab10-mediated neuroresilience. Brain expression analysis of 880 genes involved in neurodegeneration showed that Rab10+/−mice have increased activation of pathways associated with neuronal metabolism, structural integrity, neurotransmission, and neuroplasticity compared with their Rab10+/+littermates. Lower activation was observed for pathways involved in neuroinflammation and aging. We identified and validated several differentially expressed genes (DEGs), including Stx2, Stx1b, Vegfa, and Lrrc25 (downregulated) and Prkaa2, Syt4, and Grin2d (upregulated). Behavioral testing showed that Rab10+/−mice perform better in a hippocampal-dependent spatial task (object in place test), while their performance in a classical conditioning task (trace...
Supplemental Figure to Asgeirsdottir et al. manuscript entitled, "Object and place informati... more Supplemental Figure to Asgeirsdottir et al. manuscript entitled, "Object and place information processing by CA1 hippocampal neurons of C57BL/6J mice" under review at Journal of Neurophysiology.<br> Suppl. Figure 1. Hippocampal CA1 object-related firing. <b>a)</b> Representative placement of the unilateral tetrode arrays implanted over the CA1 region of the right and medial dorsal hippocampus for four mice (blue-filled circles) that object cell activity was recorded from. <b>b)</b> Representative place x firing rate maps from a CA1 place cell and a simultaneously recorded CA1 object cell during habituation 2 and test of the OR task (note difference in Hz scale). The firing rate is represented by the color-coded pixels, with red referring to the location(s) where the cell discharged at its highest rate, and blue referring to the visited locations where the cell was silent. White pixels represent areas of the arena that were unvisited by the mou...
Supplemental Figure to Asgeirsdottir et al. manuscript entitled, "Object and place informati... more Supplemental Figure to Asgeirsdottir et al. manuscript entitled, "Object and place information processing by CA1 hippocampal neurons of C57BL/6J mice" under review at Journal of Neurophysiology.<br> Suppl. Figure 1. Hippocampal CA1 object-related firing. <b>a)</b> Representative placement of the unilateral tetrode arrays implanted over the CA1 region of the right and medial dorsal hippocampus for four mice (blue-filled circles) that object cell activity was recorded from. <b>b)</b> Representative place x firing rate maps from a CA1 place cell and a simultaneously recorded CA1 object cell during habituation 2 and test of the OR task (note difference in Hz scale). The firing rate is represented by the color-coded pixels, with red referring to the location(s) where the cell discharged at its highest rate, and blue referring to the visited locations where the cell was silent. White pixels represent areas of the arena that were unvisited by the mou...
The increasing prescription of opioids is fueling an epidemic of addiction and overdose deaths. M... more The increasing prescription of opioids is fueling an epidemic of addiction and overdose deaths. Morphine is a highly addictive drug characterized by a high relapse rate - even after a long period of abstinence. Serotonin (5-HT) neurotransmission participates in the development of morphine dependence, as well as the expression of morphine withdrawal. In this study, we examined the effect of blockade of 5-HT2A receptors (5-HT2ARs) on morphine-induced behavioral sensitization and withdrawal in male mice. 5-HT2AR antagonist MDL 11,939 (0.5 mg/kg, i.p.) suppressed acute morphine (5.0 mg/kg, s.c.)-induced increase in locomotor activity. Mice received morphine (10 mg/kg, s.c.) twice a day for 3 days and then drug treatment was suspended for 5 days. On day 9, a challenge dose of morphine (10 mg/kg) was administered to induce the expression of behavioral sensitization. MDL 11,939 (0.5 mg/kg, i.p.) pretreatment suppressed the expression of morphine-induced behavioral sensitization. Another co...
Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, 2017
Background-Despite our understanding of the significance of the prefrontal cortex in the consolid... more Background-Despite our understanding of the significance of the prefrontal cortex in the consolidation of long-term memories (LTM), its role in the encoding of LTM remains elusive. Here we investigated the role of new protein synthesis in the mouse medial prefrontal cortex (mPFC) in encoding contextual fear memory. Methods-Because a change in the association of mRNAs to polyribosomes is an indicator of new protein synthesis, we assessed the changes in polyribosome-associated mRNAs in the mPFC following contextual fear conditioning (CFC) in the mouse. Differential gene expression in mPFC was identified by polyribosome profiling (n = 18). The role of new protein synthesis in mPFC was determined by focal inhibition of protein synthesis (n = 131) and by intra-prelimbic cortex manipulation (n = 56) of Homer 3, a candidate identified from polyribosome profiling. Results-We identified several mRNAs that are differentially and temporally recruited to polyribosomes in the mPFC following CFC. Inhibition of protein synthesis in the prelimbic (PL), but not in the anterior cingulate cortex (ACC) region of the mPFC immediately after CFC disrupted encoding of contextual fear memory. Intriguingly, inhibition of new protein synthesis in the PL 6 hours after CFC did not impair encoding. Furthermore, expression of Homer 3, an mRNA *
ABSTRACT The purpose of this chapter is to provide an overview of a current approach in defining ... more ABSTRACT The purpose of this chapter is to provide an overview of a current approach in defining the relationships between the firing patterns of groups of neurons recorded from the freely behaving rodent. The design and construction of a 16-channel headstage and its typical integration with a commercially available multichannel data acquisition system is described in detail. Next, the chapter examines the strategies necessary to test the behavioral significance of firing patterns of individual neurons recorded from behaving animals. A discussion is included that surveys the limitations and advantages inherent in testing how discrete behavioral events are represented in single-unit activity recorded from rodents engaged in spatial and nonspatial behaviors. To expand on the technological and theoretical approaches to establishing the relationship between single-unit activity and behavior, the rodent head direction cell system is described as one useful model system. The head direction cell is considered by many to represent the directional sense of the organism and to be essential for spatial navigation. The chapter provides a critical overview of the studies that have been conducted to date to test this relationship. In short, these are the record while the rodent performs some navigational task experiments. Examination of the results from the studies reveals that there is little clear evidence to support the view that head direction cells guide spatial navigation. The ensuing discussion addresses putative reasons for the division between the empirical data and the theory of head direction cell – behavior relations. The chapter concludes with clear suggestions for alternative experimental approaches that might better address brain–behavior relationships. A plea for increased open dialogue between the fields of behavioral analysis and systems/cellular neurophysiology emerges. Improved understanding of the contributions to the neuroscience field made by behavioral neuroscientists and those by electrophysiologists should raise the bar of modern approaches to brain–behavioral relationship studies using in vivo electrophysiological methods.
Neurotransmitter Interactions and Cognitive Function, 1992
Memory is one of the most enduring challenges in all of behavioral neuroscience. A memory “system... more Memory is one of the most enduring challenges in all of behavioral neuroscience. A memory “system” must be able to engage a diverse array of neural systems that serve perceptual, emotive, and cognitive functions. It needs to (a) access and process sensory information, (b) analyze its biological significance in a specific context, determine (c) whether, (d) how, and (e) where that information should be stored, and (f) the appropriate context in which to later use it. To appreciate the rich complexity of the process we need to examine the interplay of systems that support memory and not just focus on a single brain structure or neurotransmitter. The remnants of memory reside in circuits not synapses. To understand the drama of memory we need to listen to the dialogue of all of the characters.
Rats were trained on a radial maze and then given electrolytic lesions of the MS followed by a si... more Rats were trained on a radial maze and then given electrolytic lesions of the MS followed by a single intraseptal injection of 5 /zg of NGF. Three days later they were re-tested on the maze. They were also post-operatively tested for hyperemotionality. MS lesions severely impaired performance on the radial maze and produced increased emotionality. MS lesions also produced a general decrease in hippocampal high affinity choline transport and acetylcholinesterase staining, which was not affected by NGF administration. NGF treatment ameliorated the behavioral deficit in the radial maze but had no effect on the hyperemotionality. In order to determine whether the NGF was working to restore previously learned spatial abilities, the type of learning strategy used by the animals was also assessed. NGF treatment did not restore previously learned spatial strategies but facilitated recovery of alternative learning strategies. The reduction in cognitive deficit was also paralleled by reduced ventricular enlargement in the NGF treated rats. The present results suggest that a single injection of NGF can produce a long-lasting improvement on a cognitive task and reduce some of the injury-induced, secondary reactive changes that occur following electrolytic MS lesions.
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Papers by Robert Stackman