Summary The entorhinal cortex contains neural signals for representing self-location, including grid cells that fire in periodic locations and velocity signals that encode an animal’s speed and head direction. Recent work revealed that the size and shape of the environment influences grid patterns. Whether entorhinal velocity signals are equally influenced or provide a universal metric for self-motion across environments remains unknown. Here, we report that changes to the size and shape of the environment result in re-scaling in entorhinal speed codes. Moreover, head direction cells re-organize in an experience-dependent manner to align with the axis of environmental change. A knockout mouse model allows a dissociation of the coordination between cell types, with grid and speed, but not head direction, cells responding in concert to environmental change. These results align with predictions of grid cell attractor models and point to inherent flexibility in the coding features of multiple functionally-defined entorhinal cell types.
Caspases are a family of cysteine proteases that predominantly cleave their substrates after aspartic acid residues. Much of what we know of caspases emerged from investigation a highly conserved form of programmed cell death called apoptosis. This form of cell death is regulated by several caspases, including caspase-2, caspase-3, caspase-7, caspase-8 and caspase-9. However, these “killer” apoptotic caspases have emerged as versatile enzymes that play key roles in a wide range of non-apoptotic processes. Much of what we understand about these non-apoptotic roles is built on work investigating how “killer” caspases control a range of neuronal cell behaviors. This review will attempt to provide an up to date synopsis of these roles.
The basal forebrain (BF) is critical for the motivational recruitment of attention in response to reward-related cues. This finding is consistent with a role for the BF in encoding and transmitting motivational salience and readying prefrontal circuits for further attentional processing. We recorded local field potentials to determine connectivity between prelimbic cortex (PrL) and BF during the modulation of attention by reward-related cues. We find that theta and gamma power are robustly associated with behavior. Power in both bands is significantly lower during trials in which an incorrect behavioral response is made. We find strong coherence during responses that are significantly stronger when a correct response is made. We show that information flow is largely monodirectional from BF to and is strongest when correct responses are made. These experiments demonstrate that connectivity between BF and the PrL increases during periods of increased motivational recruitment of attentional resources.
Abstract Many cells within the entorhinal cortex (EC) fire relatively infrequently, with the majority of their spikes separated by many hundreds of milliseconds. However, most cells are seen to occasionally fire two or more spikes in quick succession. Recent evidence has shown that, in EC grid cells, “burstier” cells; cells that fire more of their spikes in bursts, have more well defined spatial characteristics than cells that fire fewer bursts. We divide the spikes fired by single cells into single spikes and “clusters” of spikes occuring within 100ms. We show that these burst “clusters” of spikes fired by cells in MEC convey more finely tuned spatial and directional information than the numerically more common single spikes. In addition, we find that introducing environmental uncertainty decreases the ratio of clusters fired to single spikes. Most crucially, we find that single spikes are less spatially precise than clusters, and these spikes are more closely entrained to LFP theta than clusters. These findings demonstrate that clusters of spikes in EC convey more specific information about space than single spikes, may reflect “certainty” about spatial position and direction, and may represent a different firing “mode” in which intraregional communication is less relevant than interregional traffic.
Decades of research have demonstrated that the hippocampus is a central structure in the function of episodic memory. The phenomenology of the hippocampus has components that could conceivably represent the “what” and “where” components of the three-part what/when/where model of episodic memory, but there is relatively little evidence of hippocampal phenomenology that could represent the “when” component on timescales longer than a few minutes. The aim of the present thesis was to investigate how the hippocampus might represent temporal information over longer timescales. In order to investigate how this might happen, the firing rate of hippocampal CA1 place cells and hippocampal EEG in the theta-band were examined over very long recordings (25-30h). It was found that the firing rate of CA1 place cells oscillated on a circadian time period, and that this firing rate was not merely entrained to light as might be expected from a signal entrained to the master oscillator in the SCN, but instead appeared to be entrained with some variable coincident with the start of recording. It was also found that the frequency but not the power of hippocampal theta rhythm oscillated in an identical fashion. It was therefore hypothesised that some variable coincident with the start of the recording sessions served as an entraining stimulus. An experiment in which animals were switched into a novel environment halfway through a 25-hour recording demonstrated that environmental novelty was not sufficient to re-entrain the observed oscillation. It was therefore hypothesised that the availability of food may be the entraining stimulus. Using a novel paradigm that involved the driving of hippocampal theta by electrical stimulation of the reticular formation, the presentation of food was disambiguated from the other variables coincident with the start of recording. It was found that the frequency and power of reticular activated theta (R.A.T) oscillated on a 25-hour cycle, and that food was a sufficient zeitgeber for this oscillation. These results are considered in a model through which the newly observed circadian modulation in place cell activity might represent a temporal “time field” in the same way as it has been hypothesised that these cells may function in a spatial context, and the association of single unit firing rate and theta frequency might represent the hippocampus engaged in memory engram storage and/or retrieval. The observed oscillations in hippocampal activity reported in the present thesis might therefore represent a mechanism through which the missing “when” component of episodic memory is represented in the hippocampus.
Abstract Many cells within the entorhinal cortex (EC) fire relatively infrequently, with the majority of their spikes separated by many hundreds of milliseconds. However, most cells are seen to occasionally fire two, three, or more spikes in quick succession. Recent evidence has shown that, in EC grid cells, “burstier” cells; cells that fire more of their spikes in bursts, have more well defined spatial characteristics than cells that fire fewer bursts. However, there is evidence that the window for considering related spikes in MEC could be as long as 100ms. Here, we divide the spikes fired by single cells into single spikes and “clusters” of spikes occuring within 100ms. We show that these burst “clusters” of spikes fired by cells in MEC convey more finely tuned spatial and directional information than the numerically more common single spikes. In addition, we find that introducing environmental uncertainty decreases the ratio of clusters fired to single spikes. Most crucially, we find that although single spikes are less spatially precise than clusters, they are more temporally precise – these spikes are more closely entrained to LFP theta than clusters. These findings demonstrate that clusters of spikes in EC convey more specific information about space than single spikes, may reflect “certainty” about spatial position and direction, and may represent a different firing “mode” in which intraregional communication is less relevant than interregional traffic.
The hippocampal formation plays a critical role in the generation of episodic memory. While the encoding of the spatial and contextual components of memory have been extensively studied, how the hippocampus encodes temporal information, especially at long time intervals, is less well understood. The activity of place cells in hippocampus has previously been shown to be modulated at a circadian time-scale, entrained by a behavioral stimulus, but not entrained by light. The experimental procedures used in the previous study of this phenomenon, however, necessarily conflated two alternative entraining stimuli, the exposure to the recording environment and the availability of food, making it impossible to distinguish between these possibilities. Here we demonstrate that the frequency of theta-band hippocampal EEG varies with a circadian period in freely moving animals and that this periodicity mirrors changes in the firing rate of hippocampal neurons. Theta activity serves, therefore, as a proxy of circadian-modulated hippocampal neuronal activity. We then demonstrate that the frequency of hippocampal theta driven by stimulation of the reticular formation also varies with a circadian period. Because this effect can be observed without having to feed the animal to encourage movement we were able to identify what stimulus entrains the circadian oscillation. We show that with reticular-activated recordings started at various times of the day the frequency of theta varies quasi-sinusoidally with a 25 h period and phase-aligned when referenced to the animal's regular feeding time, but not the recording start time. Furthermore, we show that theta frequency consistently varied with a circadian period when the data obtained from repeated recordings started at various times of the day were referenced to the start of food availability in the recording chamber. This pattern did not occur when data were referenced to the start of the recording session or to the actual time of day when this was not also related to feeding time. This double dissociation demonstrates that hippocampal theta is modulated with a circadian timescale, and that this modulation is strongly entrained by food. One interpretation of this finding is that the hippocampus is responsive to a food entrainable oscillator (FEO) that might modulate foraging behavior over circadian periods.
Down syndrome (DS) in humans is caused by trisomy of chromosome 21 and is marked by prominent difficulties in learning and memory. Decades of research have demonstrated that the hippocampus is a key structure in learning and memory, and recent work with mouse models of DS has suggested differences in hippocampal activity that may be the substrate of these differences. One of the primary functional differences in DS is thought to be an excess of GABAergic innervation from medial septum to the hippocampus. In these experiments, we probe in detail the activity of region CA1 of the hippocampus using in vivo electrophysiology in male Ts65Dn mice compared with their male nontrisomic 2N littermates. We find the spatial properties of place cells in CA1 are normal in Ts65Dn animals. However, we find that the phasic relationship of both CA1 place cells and gamma rhythms to theta rhythm in the hippocampus is profoundly altered in these mice. Since the phasic organization of place cell activity and gamma oscillations on the theta wave are thought to play a critical role in hippocampal function, the changes we observe agree with recent findings that organization of the hippocampal network is potentially of more relevance to its function than the spatial properties of place cells. SIGNIFICANCE STATEMENT Recent evidence has disrupted the view that spatial deficits are associated with place cell abnormalities. In these experiments, we record hippocampal place cells and local field potential from the Ts65Dn mouse model of Down syndrome, and find phenomenologically normal place cells, but profound changes in the association of place cells and gamma rhythms with theta rhythm, suggesting that the overall network state is critically important for hippocampal function. These findings also agree with evidence suggesting that excess inhibitory control is the cause of hippocampal dysfunction in Down syndrome. The findings also confirm new avenues for pharmacological treatment of Down syndrome.
Anxiolytics that act as GABAA agonists and those that act as 5-HT1A receptor agonists all reduce the frequency of hippocampal rhythmic slow activity (RSA). Changes in RSA have been linked to changes in behavioural inhibition and therefore anxiety – but this has not been tested with specific serotonin reuptake inhibitors, which are antidepressant and anxiolytic; therefore we tested the effects of fluoxetine on RSA and behavioural inhibition. Fluoxetine (FLU; 10 and 20 mg/kg, intraperitoneally) produced a dose-related reduction in the frequency of reticular-elicited RSA. Groups of rats received, intraperitoneally, either (i) saline, or 5 mg/kg fluoxetine, or 10 mg/kg fluoxetine; or (ii) saline, or 20 mg/kg fluoxetine, or 6.6 mg/kg of the 5-HT1A agonist buspirone (BUS) and were tested on a fixed interval 60-s schedule and a differential reinforcement of low rates 15-s schedule. FLU at 5 mg/kg produced effects similar to low doses of BUS and other anxiolytics. FLU (10 and 20 mg/kg) produced effects more like those reported earlier for higher doses of BUS. These results continue to link anxiolysis, RSA and behavioural inhibition, and suggest that serotonergic anxiolytics share some of the central actions of GABAergic anxiolytics, but at higher doses, administered acutely, have distinct side effects that can obscure their anxiolytic action in behavioural tasks.
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