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• W3043853885 abstract "•Prenatal alcohol exposure reduces place field spatial tuning and stability•Prenatal alcohol exposure decreases place field directionality on the linear track•Prenatal alcohol exposure increases control of place fields by a proximal cue•Prenatal alcohol exposure slows theta oscillations and alters phase precession Prenatal alcohol exposure (PAE) leads to profound deficits in spatial memory and synaptic and cellular alterations to the hippocampus that last into adulthood. Neurons in the hippocampus called place cells discharge as an animal enters specific places in an environment, establish distinct ensemble codes for familiar and novel places, and are modulated by local theta rhythms. Spatial memory is thought to critically depend on the integrity of hippocampal place cell firing. Therefore, we tested the hypothesis that hippocampal place cell firing is impaired after PAE by performing in vivo recordings from the hippocampi (CA1 and CA3) of moderate PAE and control adult rats. Our results show that hippocampal CA3 neurons from PAE rats have reduced spatial tuning. Second, CA1 and CA3 neurons from PAE rats are less likely to orthogonalize their firing between directions of travel on a linear track and between changes in contextual stimuli in an open arena compared to control neurons. Lastly, reductions in the number of hippocampal place cells exhibiting significant theta rhythmicity and phase precession were observed, which may suggest changes to hippocampal microcircuit function. Together, the reduced spatial tuning and sensitivity to contextual changes provide a neural systems-level mechanism to explain spatial memory impairment after moderate PAE. Prenatal alcohol exposure (PAE) leads to profound deficits in spatial memory and synaptic and cellular alterations to the hippocampus that last into adulthood. Neurons in the hippocampus called place cells discharge as an animal enters specific places in an environment, establish distinct ensemble codes for familiar and novel places, and are modulated by local theta rhythms. Spatial memory is thought to critically depend on the integrity of hippocampal place cell firing. Therefore, we tested the hypothesis that hippocampal place cell firing is impaired after PAE by performing in vivo recordings from the hippocampi (CA1 and CA3) of moderate PAE and control adult rats. Our results show that hippocampal CA3 neurons from PAE rats have reduced spatial tuning. Second, CA1 and CA3 neurons from PAE rats are less likely to orthogonalize their firing between directions of travel on a linear track and between changes in contextual stimuli in an open arena compared to control neurons. Lastly, reductions in the number of hippocampal place cells exhibiting significant theta rhythmicity and phase precession were observed, which may suggest changes to hippocampal microcircuit function. Together, the reduced spatial tuning and sensitivity to contextual changes provide a neural systems-level mechanism to explain spatial memory impairment after moderate PAE. Prenatal alcohol exposure (PAE) is detrimental to the developing nervous system [1Guerri C. Sanchis R. Acetaldehyde and alcohol levels in pregnant rats and their fetuses.Alcohol. 1985; 2: 267-270Crossref PubMed Scopus (0) Google Scholar] and remains one of the most common developmental insults [2Day N.L. Leech S.L. Richardson G.A. Cornelius M.D. Robles N. Larkby C. Prenatal alcohol exposure predicts continued deficits in offspring size at 14 years of age.Alcohol. Clin. Exp. Res. 2002; 26: 1584-1591Crossref PubMed Google Scholar, 3Green C.R. Mihic A.M. Nikkel S.M. Stade B.C. Rasmussen C. Munoz D.P. Reynolds J.N. 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These receptive fields are referred to as place fields, and their precise population activity has been thought to form a “cognitive map,” giving an animal a sense of past, present, and future locations [16O’Keefe J. Nadel L. The Hippocampus as a Cognitive Map. Clarendon, 1978Google Scholar]. Although the correlation between a place cell’s firing rate and location is commonly referred to as rate coding, phase or temporal coding co-occurs, whereby spikes from single theta-rhythmic place cells systematically phase shift across successive theta cycles in a phenomenon known as theta phase precession [17O’Keefe J. Recce M.L. Phase relationship between hippocampal place units and the EEG theta rhythm.Hippocampus. 1993; 3: 317-330Crossref PubMed Google Scholar]. Moderate PAE during the first and second trimester impairs spatial behavior (reviewed in [7Harvey R.E. Berkowitz L.E. Hamilton D.A. Clark B.J. The effects of developmental alcohol exposure on the neurobiology of spatial processing.Neurosci. Biobehav. Rev. 2019; 107: 775-794Crossref PubMed Scopus (1) Google Scholar]). In the Morris water task, rats with moderate PAE are generally unable to quickly adapt to changes in task demands, such as a change in the escape location in the water task or recalling a previously learned location [9Sutherland R.J. McDonald R.J. Savage D.D. Prenatal exposure to moderate levels of ethanol can have long-lasting effects on learning and memory in adult offspring.Psychobiology. 2000; 28: 532-539Google Scholar, 18Hamilton D.A. Barto D. Rodriguez C.I. Magcalas C.M. Fink B.C. Rice J.P. Bird C.W. Davies S. Savage D.D. Effects of moderate prenatal ethanol exposure and age on social behavior, spatial response perseveration errors and motor behavior.Behav. Brain Res. 2014; 269: 44-54Crossref PubMed Scopus (49) Google Scholar, 19Rodriguez C.I. Magcalas C.M. Barto D. Fink B.C. Rice J.P. Bird C.W. Davies S. Pentkowski N.S. Savage D.D. Hamilton D.A. Effects of sex and housing on social, spatial, and motor behavior in adult rats exposed to moderate levels of alcohol during prenatal development.Behav. Brain Res. 2016; 313: 233-243Crossref PubMed Scopus (11) Google Scholar, 20Savage D.D. Becher M. de la Torre A.J. Sutherland R.J. Dose-dependent effects of prenatal ethanol exposure on synaptic plasticity and learning in mature offspring.Alcohol. Clin. Exp. Res. 2002; 26: 1752-1758Crossref PubMed Google Scholar]. In dry land tasks, moderate PAE impairs spatial discrimination [21Brady M.L. Allan A.M. Caldwell K.K. A limited access mouse model of prenatal alcohol exposure that produces long-lasting deficits in hippocampal-dependent learning and memory.Alcohol. Clin. Exp. Res. 2012; 36: 457-466Crossref PubMed Scopus (0) Google Scholar, 22Sanchez L.M. Goss J. Wagner J. Davies S. Savage D.D. Hamilton D.A. Clark B.J. Moderate prenatal alcohol exposure impairs performance by adult male rats in an object-place paired-associate task.Behav. Brain Res. 2019; 360: 228-234Crossref PubMed Scopus (3) Google Scholar], with greater deficits observed when the discrimination involves subtle differences in spatial context [21Brady M.L. Allan A.M. Caldwell K.K. A limited access mouse model of prenatal alcohol exposure that produces long-lasting deficits in hippocampal-dependent learning and memory.Alcohol. Clin. Exp. Res. 2012; 36: 457-466Crossref PubMed Scopus (0) Google Scholar]. Importantly, spatial flexibility and discrimination are thought to be reliant on functionally intact hippocampi and have been associated with HPC place cell activity [23Behrens T.E.J. Muller T.H. Whittington J.C.R. Mark S. Baram A.B. Stachenfeld K.L. Kurth-Nelson Z. What is a cognitive map? Organizing knowledge for flexible behavior.Neuron. 2018; 100: 490-509Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar, 24Rubin A. Yartsev M.M. Ulanovsky N. Encoding of head direction by hippocampal place cells in bats.J. Neurosci. 2014; 34: 1067-1080Crossref PubMed Scopus (43) Google Scholar]. Moderate PAE can also lead to reductions in long-term potentiation (LTP), which is considered to be a mechanism by which increases in synaptic strength support associative learning [25Bliss T.V. Lomo T. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path.J. Physiol. 1973; 232: 331-356Crossref PubMed Scopus (4500) Google Scholar, 26McNaughton B.L. Morris R.G.M. Hippocampal synaptic enhancement and information storage within a distributed memory system.Trends Neurosci. 1987; 10: 408-415Abstract Full Text PDF Scopus (867) Google Scholar]. 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Parallel instabilities of long-term potentiation, place cells, and learning caused by decreased protein kinase A activity.J. Neurosci. 2000; 20: 8096-8102Crossref PubMed Google Scholar] and their failure to remap or discriminate spatial contexts [37McHugh T.J. Jones M.W. Quinn J.J. Balthasar N. Coppari R. Elmquist J.K. Lowell B.B. Fanselow M.S. Wilson M.A. Tonegawa S. Dentate gyrus NMDA receptors mediate rapid pattern separation in the hippocampal network.Science. 2007; 317: 94-99Crossref PubMed Scopus (610) Google Scholar] (discussed in [38Yassa M.A. Stark C.E. Pattern separation in the hippocampus.Trends Neurosci. 2011; 34: 515-525Abstract Full Text Full Text PDF PubMed Scopus (597) Google Scholar]). Thus, it is expected that HPC-dependent spatial discrimination, such as how place cells discriminate directions of locomotion on linear track environments [39Battaglia F.P. Sutherland G.R. McNaughton B.L. Local sensory cues and place cell directionality: additional evidence of prospective coding in the hippocampus.J. Neurosci. 2004; 24: 4541-4550Crossref PubMed Scopus (98) Google Scholar, 40Frank L.M. Stanley G.B. Brown E.N. Hippocampal plasticity across multiple days of exposure to novel environments.J. Neurosci. 2004; 24: 7681-7689Crossref PubMed Scopus (219) Google Scholar, 41McNaughton B.L. Barnes C.A. O’Keefe J. The contributions of position, direction, and velocity to single unit activity in the hippocampus of freely-moving rats.Exp. Brain Res. 1983; 52: 41-49Crossref PubMed Scopus (672) Google Scholar] or between spatial context changes [38Yassa M.A. Stark C.E. Pattern separation in the hippocampus.Trends Neurosci. 2011; 34: 515-525Abstract Full Text Full Text PDF PubMed Scopus (597) Google Scholar], will be disrupted following PAE. The linkage between spatial behavior and HPC structural differences after moderate PAE is poorly understood but is likely to involve alterations in HPC place cell activity [7Harvey R.E. Berkowitz L.E. Hamilton D.A. Clark B.J. The effects of developmental alcohol exposure on the neurobiology of spatial processing.Neurosci. Biobehav. Rev. 2019; 107: 775-794Crossref PubMed Scopus (1) Google Scholar]. Although previous studies have shown acute alcohol exposure in adult rats disrupts HPC place cell activity [42Matthews D.B. Simson P.E. Best P.J. Ethanol alters spatial processing of hippocampal place cells: a mechanism for impaired navigation when intoxicated.Alcohol. Clin. Exp. Res. 1996; 20: 404-407Crossref PubMed Scopus (0) Google Scholar, 43White A.M. Best P.J. Effects of ethanol on hippocampal place-cell and interneuron activity.Brain Res. 2000; 876: 154-165Crossref PubMed Scopus (0) Google Scholar], we are unaware of prior work investigating the impact of developmental alcohol exposure on HPC place cell activity. Thus, in the present study, we first hypothesized that, because PAE impairs spatial behavior and HPC function, place cells will have altered spatial tuning, temporal-spatial stability, theta rhythmicity, and phase coding in PAE offspring. Second, because previous studies report decreased LTP, we hypothesize that place cells from rats with PAE will have decreased directional discrimination on a linear track environment and differential rate and spatial tuning effects following contextual stimuli changes between sessions. Therefore, we recorded from neurons from HPC CA1 and CA3 of adult rats with moderate PAE (BAC: 60.8 ± 5.8 mg/dL) [44Davies S. Ballesteros-Merino C. Allen N.A. Porch M.W. Pruitt M.E. Christensen K.H. Rosenberg M.J. Savage D.D. Impact of moderate prenatal alcohol exposure on histaminergic neurons, histidine decarboxylase levels and histamine H2 receptors in adult rat offspring.Alcohol. 2019; 76: 47-57Crossref PubMed Scopus (4) Google Scholar] that occurred throughout gestation, and saccharin control rats over three environmental conditions: a linear track; an open field cylinder; and an open field cylinder with a proximal cue rotation (Figures 1A and 1B ). Although firing responses to spatial features have been observed to differ between CA1 and CA3 subregions [45Lee I. Yoganarasimha D. Rao G. Knierim J.J. Comparison of population coherence of place cells in hippocampal subfields CA1 and CA3.Nature. 2004; 430: 456-459Crossref PubMed Scopus (297) Google Scholar, 46Leutgeb S. Leutgeb J.K. Treves A. Moser M.B. Moser E.I. Distinct ensemble codes in hippocampal areas CA3 and CA1.Science. 2004; 305: 1295-1298Crossref PubMed Scopus (492) Google Scholar, 47Park E. Dvorak D. Fenton A.A. Ensemble place codes in hippocampus: CA1, CA3, and dentate gyrus place cells have multiple place fields in large environments.PLoS ONE. 2011; 6: e22349Crossref PubMed Scopus (45) Google Scholar, 48Roth E.D. Yu X. Rao G. Knierim J.J. Functional differences in the backward shifts of CA1 and CA3 place fields in novel and familiar environments.PLoS ONE. 2012; 7: e36035Crossref PubMed Scopus (0) Google Scholar, 49Mizuseki K. Royer S. Diba K. Buzsáki G. Activity dynamics and behavioral correlates of CA3 and CA1 hippocampal pyramidal neurons.Hippocampus. 2012; 22: 1659-1680Crossref PubMed Scopus (94) Google Scholar], the following analyses focus on assessing intraregional comparisons between PAE and control cell populations. Our results show that HPC CA3 neurons from PAE rats have reduced spatial tuning and are less likely to display theta phase precession. Second, CA1 and CA3 neurons from PAE rats have reduced theta frequencies and are less likely to orthogonalize their firing between directions of travel on the linear track and in contextual stimuli changes between the cylinder sessions compared to control animals. To explore how HPC spatial encoding is affected following moderate PAE, we recorded populations of HPC neurons from 9 control and 8 PAE adult male rats as they ran laps on a linear track or randomly foraged for scattered food in a cylindrical enclosure (Figures 1A and 1B). PAE did not disrupt the ability to perform laps on the linear track, with no group differences observed in the number of laps completed per session (control median: 41; PAE median: 40). Similarly, there were no significant group differences in trial-averaged running speed on the linear track or in the cylinder (discussed in section Speed-Modulated Intrinsic Theta Frequency). These findings are consistent with previous studies that have reported unaffected locomotor behaviors following moderate PAE [21Brady M.L. Allan A.M. Caldwell K.K. A limited access mouse model of prenatal alcohol exposure that produces long-lasting deficits in hippocampal-dependent learning and memory.Alcohol. Clin. Exp. Res. 2012; 36: 457-466Crossref PubMed Scopus (0) Google Scholar, 50Patten A.R. Sawchuk S. Wortman R.C. Brocardo P.S. Gil-Mohapel J. Christie B.R. Prenatal ethanol exposure impairs temporal ordering behaviours in young adult rats.Behav. Brain Res. 2016; 299: 81-89Crossref PubMed Scopus (6) Google Scholar]. Despite similar behavioral metrics, impairments in the spatial tuning, measured by spatial information content and sparsity, were evident in PAE place fields. CA3 place fields in PAE animals had significantly lower spatial information and higher sparsity in both linear track and cylinder tests (p < 0.001; Wilcoxon rank-sum [WRS]; effect sizes [r] ≥0.19; Figure 1C). In contrast, we did not observe group differences in spatial tuning by CA1 place fields. We also investigated group differences in peak firing rate and spatial coherence, which measures the consistency of spiking across the place field. In PAE rats, CA1 and CA3 place cells had significantly diminished peak firing rates in both tasks (p < 0.05; WRS; effect sizes [r] ≥0.10; Figure 1C). Average firing rates and bursting across sessions are shown in Figure S1. Furthermore, CA1 and CA3 firing fields in PAE rats had significantly lower spatial coherence in both tasks (p < 0.05; WRS; effect sizes [r] ≥0.08; Figure 1C). However, it is important to note that the extent of these two CA1 differences were small (effect sizes [r] 0.10–0.14). Together, these results indicate that peak firing and coherence in both CA1 and CA3 were affected by PAE and measures of spatial tuning were affected in CA3. To investigate whether spatial tuning was stable over time, we evaluated the within-session spatial stability of place fields on the linear track and cylinder environments (Figure 2). Within-session stability was measured by calculating the spatial correlation between rate maps generated from the first half of the recording session versus the second half. CA1 and CA3 PAE place cells had lower within-session stability compared to control CA1 and CA3 place cells in both linear track and cylinder environments (p < 0.001; WRS; effect sizes [r] ≥0.11; Figure 2). To ensure that these results were not due to poor sampling of the environment, we assessed running speed and the amount of exploration across the two halves of each recording session (Figure S2). Although running speeds and amount of exploration was similar between groups in the cylinder, running speeds from PAE rats on the linear track tended to slightly increase (1 cm/s) from the first to second half of each session compared to control rats. However, because place cell firing properties tend to scale with running speed [51Geisler C. Robbe D. Zugaro M. Sirota A. Buzsáki G. Hippocampal place cell assemblies are speed-controlled oscillators.Proc. Natl. Acad. Sci. USA. 2007; 104: 8149-8154Crossref PubMed Scopus (151) Google Scholar, 52McClain K. Tingley D. Heeger D.J. Buzsáki G. Position-theta-phase model of hippocampal place cell activity applied to quantification of running speed modulation of firing rate.Proc. Natl. Acad. Sci. 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However, when the animal’s path is restricted, such as in a linear track, firing rates and peak firing locations significantly differ in opposite directions of travel [39Battaglia F.P. Sutherland G.R. McNaughton B.L. Local sensory cues and place cell directionality: additional evidence of prospective coding in the hippocampus.J. Neurosci. 2004; 24: 4541-4550Crossref PubMed Scopus (98) Google Scholar, 41McNaughton B.L. Barnes C.A. O’Keefe J. The contributions of position, direction, and velocity to single unit activity in the hippocampus of freely-moving rats.Exp. Brain Res. 1983; 52: 41-49Crossref PubMed Scopus (672) Google Scholar, 54Muller R.U. Bostock E. Taube J.S. Kubie J.L. On the directional firing properties of hippocampal place cells.J. Neurosci. 1994; 14: 7235-7251Crossref PubMed Google Scholar]. As a result, place cells express directionality in their firing such that their representation of the track in the two directions are distinct or orthogonal (Figures 3A and 3B ). Thus, to determine whether directional firing on the linear track was impaired after PAE, we quantified place cell directionality in two ways: first by correlating rate maps for place fields in each direction of travel and by computing a directionality index that quantifies the magnitude of firing rate differences between each direction of travel. We found that spatial correlations between the two running directions were significantly higher for CA1 PAE place cells (p < 0.01; WRS; effect size [r] = 0.17; Figures 3A–3C) but were similar across the two groups for CA3 place cells (p > 0.05; WRS). Indicating that, following PAE, CA1 place cells on the linear track are less likely to spatially orthogonalize. Similarly, the directionality index between the two running directions was significantly lower for CA3 PAE place cells (p < 0.001; WRS; effect size [r] = 0.13; Figures 3A–3D), indicating that CA3 place cells are less likely to orthogonalize their firing rates on the linear track in PAE rats. Together, mechanisms underlying place cell directionality are disrupted, suggesting that rats with PAE are unable to form unique complex representations that aid in the disambiguation of different environmental directions. We next sought to determine the sensitivity of PAE place cells to landmark manipulation by rotating a cue located along the wall of the open-field cylinder environment (Figure 4A). Importantly, we did not disorient rats between sessions so as to not disrupt their internal path integrator, in effect creating a contextual change by inducing a mismatch between the previously experienced and the rotated cue position [65Zittrell F. 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• W3043853885 title "Altered Hippocampal Place Cell Representation and Theta Rhythmicity following Moderate Prenatal Alcohol Exposure" @default.
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