Dentate Gyrus Somatostatin Cells are Required for Contextual Discrimination During Episodic Memory Encoding.

Memory systems ought to store and discriminate representations of similar experiences in order to efficiently guide future decisions. This problem is solved by pattern separation, implemented in the dentate gyrus (DG) by granule cells to support episodic memory formation. Pattern separation is enabled by tonic inhibitory bombardment generated by multiple GABAergic cell populations that strictly maintain low activity levels in granule cells. Somatostatin-expressing cells are one of those interneuron populations, selectively targeting the distal dendrites of granule cells, where cortical multimodal information reaches the DG. Nonetheless, somatostatin cells have very low connection probability and synaptic efficacy with both granule cells and other interneuron types. Hence, the role of somatostatin cells in DG circuitry, particularly in the context of pattern separation, remains uncertain. Here, by using optogenetic stimulation and behavioral tasks in mice, we demonstrate that somatostatin cells are required for the acquisition of both contextual and spatial overlapping memories.

Coordinated prefrontal-hippocampal activity and navigation strategy-related prefrontal firing during spatial memory formation.

Learning the location of relevant places in the environment is crucial for survival. Such capacity is supported by a distributed network comprising the prefrontal cortex and hippocampus, yet it is not fully understood how these structures cooperate during spatial reference memory formation. Hence, we examined neural activity in the prefrontal-hippocampal circuit in mice during acquisition of spatial reference memory. We found that interregional oscillatory coupling increased with learning, specifically in the slow-gamma frequency (20 to 40 Hz) band during spatial navigation. In addition, mice used both spatial and nonspatial strategies to navigate and solve the task, yet prefrontal neuronal spiking and oscillatory phase coupling were selectively enhanced in the spatial navigation strategy. Lastly, a representation of the behavioral goal emerged in prefrontal spiking patterns exclusively in the spatial navigation strategy. These results suggest that reference memory formation is supported by enhanced cortical connectivity and evolving prefrontal spiking representations of behavioral goals.

Basal Forebrain Gating by Somatostatin Neurons Drives Prefrontal Cortical Activity.

The basal forebrain provides modulatory input to the cortex regulating brain states and cognitive processing. Somatostatin-expressing neurons constitute a heterogeneous GABAergic population known to functionally inhibit basal forebrain cortically projecting cells thus favoring sleep and cortical synchronization. However, it remains unclear if somatostatin cells can regulate population activity patterns in the basal forebrain and modulate cortical dynamics. Here, we demonstrate that somatostatin neurons regulate the corticopetal synaptic output of the basal forebrain impinging on cortical activity and behavior. Optogenetic inactivation of somatostatin neurons in vivo rapidly modified neural activity in the basal forebrain, with the consequent enhancement and desynchronization of activity in the prefrontal cortex, reflected in both neuronal spiking and network oscillations. Cortical activation was partially dependent on cholinergic transmission, suppressing slow waves and potentiating gamma oscillations. In addition, recruitment dynamics was cell type-specific, with interneurons showing similar temporal profiles, but stronger responses than pyramidal cells. Finally, optogenetic stimulation of quiescent animals during resting periods prompted locomotor activity, suggesting generalized cortical activation and increased arousal. Altogether, we provide physiological and behavioral evidence indicating that somatostatin neurons are pivotal in gating the synaptic output of the basal forebrain, thus indirectly controlling cortical operations via both cholinergic and non-cholinergic mechanisms.

Prenatal Stress Produces Persistence of Remote Memory and Disrupts Functional Connectivity in the Hippocampal-Prefrontal Cortex Axis.

Prenatal stress is a risk factor for the development of neuropsychiatric disorders, many of which are commonly characterized by an increased persistence of aversive remote memory. Here, we addressed the effect of prenatal stress on both memory consolidation and functional connectivity in the hippocampal-prefrontal cortex axis, a dynamical interplay that is critical for mnemonic processing. Pregnant mice of the C57BL6 strain were subjected to restraint stressed during the last week of pregnancy, and male offspring were behaviorally tested at adulthood for recent and remote spatial memory performance in the Barnes Maze test under an aversive context. Prenatal stress did not affect the acquisition or recall of recent memory. In contrast, it produced the persistence of remote spatial memory. Memory persistence was not associated with alterations in major network rhythms, such as hippocampal sharp-wave ripples (SWRs) or neocortical spindles. Instead, it was associated with a large decrease in the basal discharge activity of identified principal neurons in the medial prefrontal cortex (mPFC) as measured in urethane anesthetized mice. Furthermore, functional connectivity was disrupted, as the temporal coupling between neuronal discharge in the mPFC and hippocampal SWRs was decreased by prenatal stress. These results could be relevant to understand the biological basis of the persistence of aversive remote memories in stress-related disorders.

Bootstrap testing for cross-correlation under low firing activity.

A new cross-correlation synchrony index for neural activity is proposed. The index is based on the integration of the kernel estimation of the cross-correlation function. It is used to test for the dynamic synchronization levels of spontaneous neural activity under two induced brain states: sleep-like and awake-like. Two bootstrap resampling plans are proposed to approximate the distribution of the test statistics. The results of the first bootstrap method indicate that it is useful to discern significant differences in the synchronization dynamics of brain states characterized by a neural activity with low firing rate. The second bootstrap method is useful to unveil subtle differences in the synchronization levels of the awake-like state, depending on the activation pathway.

Spatiotemporal Gait Patterns During Overt and Covert Evaluation in Patients With Parkinson´s Disease and Healthy Subjects: Is There a Hawthorne Effect?

Parkinson's disease (PD) and aging lead to gait impairments. Some of the disturbances of gait are focused on step length, cadence, and temporal variability of gait cycle. Under experimental conditions gait can be overtly evaluated, but patients with PD are prone to expectancy effects; thus it seems relevant to determine if such evaluation truly reflects the spontaneous gait pattern in such patients, and also in healthy subjects. Thirty subjects (15 subjects with PD and 15 healthy control subjects) were asked to walk using their natural, preferred gait pattern. In half of the trials subjects were made aware that they were being evaluated (overt evaluation), while in the rest of the trials the evaluation was performed covertly (covert evaluation). During covert evaluation the gait pattern was modified in all groups. Gait speed was significantly increased (P = .022); step cadence and average step length were also significantly modified, the average step length increased (P = .002) and the cadence was reduced (P ≤ .001). Stride cycle time variability was unchanged significantly (P = .084). These changes were not significantly different compared between elderly and young healthy controls either. Due to the small sample size, a note of caution is in order; however, the significant results suggest that covert evaluation of gait might be considered to complement experimental evaluations of gait.

The effects of expectancy on corticospinal excitability: passively preparing to observe a movement.

The corticospinal tract excitability is modulated when preparing movements. Earlier to movement execution, the excitability of the spinal cord increases waiting for supraspinal commands to release the movement. Movement execution and movement observation share processes within the motor system, although movement observation research has focused on processes later to movement onset. We used single and paired pulse transcranial magnetic stimulation on M1 (n = 12), and electrical cervicomedullary stimulation (n = 7), to understand the modulation of the corticospinal system during the "preparation" to observe a third person's movement. Subjects passively observed a hand that would remain still or make an index finger extension. The observer's corticospinal excitability rose when "expecting to see a movement" vs. when "expecting to see a still hand." The modulation took origin at a spinal level and not at the corticocortical networks explored. We conclude that expectancy of seeing movements increases the excitability of the spinal cord.

Functional two-way analysis of variance and bootstrap methods for neural synchrony analysis.

BACKGROUND: Pairwise association between neurons is a key feature in understanding neural coding. Statistical neuroscience provides tools to estimate and assess these associations. In the mammalian brain, activating ascending pathways arise from neuronal nuclei located at the brainstem and at the basal forebrain that regulate the transition between sleep and awake neuronal firing modes in extensive regions of the cerebral cortex, including the primary visual cortex, where neurons are known to be selective for the orientation of a given stimulus. In this paper, the estimation of neural synchrony as a function of time is studied in data obtained from anesthetized cats. A functional data analysis of variance model is proposed. Bootstrap statistical tests are introduced in this context; they are useful tools for the study of differences in synchrony strength regarding 1) transition between different states (anesthesia and awake), and 2) affinity given by orientation selectivity. RESULTS: An analysis of variance model for functional data is proposed for neural synchrony curves, estimated with a cross-correlation based method. Dependence arising from the experimental setting needs to be accounted for. Bootstrap tests allow the identification of differences between experimental conditions (modes of activity) and between pairs of neurons formed by cells with different affinities given by their preferred orientations. In our test case, interactions between experimental conditions and preferred orientations are not statistically significant. CONCLUSIONS: The results reflect the effect of different experimental conditions, as well as the affinity regarding orientation selectivity in neural synchrony and, therefore, in neural coding. A cross-correlation based method is proposed that works well under low firing activity. Functional data statistical tools produce results that are useful in this context. Dependence is shown to be necessary to account for, and bootstrap tests are an appropriate method with which to do so.

Sleep-dependent decorrelation of hippocampal spatial representations.

Neuronal ensembles are crucial for episodic memory and spatial mapping. Sleep, particularly non-REM (NREM), is vital for memory consolidation, as it triggers plasticity mechanisms through brain oscillations that reactivate neuronal ensembles. Here, we assessed their role in consolidating hippocampal spatial representations during sleep. We recorded hippocampus activity in rats performing a spatial object-place recognition (OPR) memory task, during encoding and retrieval periods, separated by intervening sleep. Successful OPR retrieval correlated with NREM duration, during which cortical oscillations decreased in power and density as well as neuronal spiking, suggesting global downregulation of network excitability. However, neurons encoding specific spatial locations (i.e., place cells) or objects during OPR showed stronger synchrony with brain oscillations compared to non-encoding neurons, and the stability of spatial representations decreased proportionally with NREM duration. Our findings suggest that NREM sleep may promote flexible remapping in hippocampal ensembles, potentially aiding memory consolidation and adaptation to novel spatial contexts.

Dominance hierarchy regulates social behavior during spatial movement.

Rodents establish dominance hierarchy as a social ranking system in which one subject acts as dominant over all the other subordinate individuals. Dominance hierarchy regulates food access and mating opportunities, but little is known about its significance in other social behaviors, for instance during collective navigation for foraging or migration. Here, we implemented a simplified goal-directed spatial task in mice, in which animals navigated individually or collectively with their littermates foraging for food. We compared between conditions and found that the social condition exerts significant influence on individual displacement patterns, even when efficient navigation rules leading to reward had been previously learned. Thus, movement patterns and consequent task performance were strongly dependent on contingent social interactions arising during collective displacement, yet their influence on individual behavior was determined by dominance hierarchy. Dominant animals did not behave as leaders during collective displacement; conversely, they were most sensitive to the social environment adjusting their performance accordingly. Social ranking in turn was associated with specific spontaneous neural activity patterns in the prefrontal cortex and hippocampus, with dominant mice showing higher firing rates, larger ripple oscillations, and stronger neuronal entrainment by ripples than subordinate animals. Moreover, dominant animals selectively increased their cortical spiking activity during collective movement, while subordinate mice did not modify their firing rates, consistent with dominant animals being more sensitive to the social context. These results suggest that dominance hierarchy influences behavioral performance during contingent social interactions, likely supported by the coordinated activity in the hippocampal-prefrontal circuit.

c-Abl tyrosine kinase down-regulation as target for memory improvement in Alzheimer's disease.

Background: Growing evidence suggests that the non-receptor tyrosine kinase, c-Abl, plays a significant role in the pathogenesis of Alzheimer's disease (AD). Here, we analyzed the effect of c-Abl on the cognitive performance decline of APPSwe/PSEN1ΔE9 (APP/PS1) mouse model for AD. Methods: We used the conditional genetic ablation of c-Abl in the brain (c-Abl-KO) and pharmacological treatment with neurotinib, a novel allosteric c-Abl inhibitor with high brain penetrance, imbued in rodent's chow. Results: We found that APP/PS1/c-Abl-KO mice and APP/PS1 neurotinib-fed mice had improved performance in hippocampus-dependent tasks. In the object location and Barnes-maze tests, they recognized the displaced object and learned the location of the escape hole faster than APP/PS1 mice. Also, APP/PS1 neurotinib-fed mice required fewer trials to reach the learning criterion in the memory flexibility test. Accordingly, c-Abl absence and inhibition caused fewer amyloid plaques, reduced astrogliosis, and preserved neurons in the hippocampus. Discussion: Our results further validate c-Abl as a target for AD, and the neurotinib, a novel c-Abl inhibitor, as a suitable preclinical candidate for AD therapies.

Optogenetic Suppression of Lateral Septum Somatostatin Neurons Enhances Hippocampus Cholinergic Theta Oscillations and Local Synchrony.

The septal complex regulates both motivated and innate behaviors, chiefly by the action of its diverse population of long-range projection neurons. A small population of somatostatin-expressing GABAergic cells in the lateral septum projects deep into subcortical regions, yet on its way it also targets neighboring medial septum neurons that profusely innervate cortical targets by ascending synaptic pathways. Here, we used optogenetic stimulation and extracellular recordings in acutely anesthetized transgenic mice to show that lateral septum somatostatin neurons can disinhibit the cholinergic septo-hippocampal pathway, thus enhancing the amplitude and synchrony of theta oscillations while depressing sharp-wave ripple episodes in the dorsal hippocampus. These results suggest that septal somatostatin cells can recruit ascending cholinergic pathways to promote hippocampal theta oscillations.

Basal forebrain somatostatin cells differentially regulate local gamma oscillations and functionally segregate motor and cognitive circuits.

The basal forebrain delivers extensive axonal projections to the cortical mantle regulating brain states and cognitive processing. Recent evidence has established the basal forebrain as a subcortical node of the default mode network that directionally influences cortical dynamics trough gamma oscillations, yet their synaptic origin has not been established. Here, we used optogenetic stimulation and in vivo recordings of transgenic mice to show that somatostatin neurons exert an anatomically specialized role in the coordination of subcortical gamma oscillations of the rostral basal forebrain. Indeed, the spike timing of somatostatin cells was tightly correlated with gamma oscillations in the ventral pallidum, but not in the medial septum. Consequently, optogenetic inactivation of somatostatin neurons selectively disrupted the amplitude and coupling of gamma oscillations only in the ventral pallidum. Moreover, photosupression of somatostatin cells produced specific behavioral interferences, with the ventral pallidum regulating locomotor speed and the medial septum modulating spatial working memory. Altogether, these data suggest that basal forebrain somatostatin cells can selectively synchronize local neuronal networks in the gamma band directly impinging on cortical dynamics and behavioral performance. This further supports the role of the basal forebrain as a subcortical switch commanding transitions between internally and externally oriented brain states.

Reactive Disruption of the Hippocampal Neurogenic Niche After Induction of Seizures by Injection of Kainic Acid in the Amygdala.

Adult neurogenesis persists in the adult hippocampus due to the presence of multipotent neural stem cells (NSCs). Hippocampal neurogenesis is involved in a range of cognitive functions and is tightly regulated by neuronal activity. NSCs respond promptly to physiological and pathological stimuli altering their neurogenic and gliogenic potential. In a mouse model of mesial temporal lobe epilepsy (MTLE), seizures triggered by the intrahippocampal injection of the glutamate receptor agonist kainic acid (KA) induce NSCs to convert into reactive NSCs (React-NSCs) which stop producing new neurons and ultimately generate reactive astrocytes thus contributing to the development of hippocampal sclerosis and abolishing neurogenesis. We herein show how seizures triggered by the injection of KA in the amygdala, an alternative model of MTLE which allows parallel experimental manipulation in the dentate gyrus, also trigger the induction of React-NSCs and provoke the disruption of the neurogenic niche resulting in impaired neurogenesis. These results highlight the sensitivity of NSCs to the surrounding neuronal circuit activity and demonstrate that the induction of React-NSCs and the disruption of the neurogenic niche are not due to the direct effect of KA in the hippocampus. These results also suggest that neurogenesis might be lost in the hippocampus of patients with MTLE. Indeed we provide results from human MTLE samples absence of cell proliferation, of neural stem cell-like cells and of neurogenesis.

Midline thalamic neurons are differentially engaged during hippocampus network oscillations.

The midline thalamus is reciprocally connected with the medial temporal lobe, where neural circuitry essential for spatial navigation and memory formation resides. Yet, little information is available on the dynamic relationship between activity patterns in the midline thalamus and medial temporal lobe. Here, we report on the functional heterogeneity of anatomically-identified thalamic neurons and the differential modulation of their activity with respect to dorsal hippocampal rhythms in the anesthetized mouse. Midline thalamic neurons expressing the calcium-binding protein calretinin, irrespective of their selective co-expression of calbindin, discharged at overall low levels, did not increase their activity during hippocampal theta oscillations, and their firing rates were inhibited during hippocampal sharp wave-ripples. Conversely, thalamic neurons lacking calretinin discharged at higher rates, increased their activity during hippocampal theta waves, but remained unaffected during sharp wave-ripples. Our results indicate that the midline thalamic system comprises at least two different classes of thalamic projection neuron, which can be partly defined by their differential engagement by hippocampal pathways during specific network oscillations that accompany distinct behavioral contexts. Thus, different midline thalamic neuronal populations might be selectively recruited to support distinct stages of memory processing, consistent with the thalamus being pivotal in the dialogue of cortical circuits.

Effects of movement imitation training in Parkinson's disease: A virtual reality pilot study.

BACKGROUND: Hypometria is a clinical motor sign in Parkinson's disease. Its origin likely emerges from basal ganglia dysfunction, leading to an impaired control of inhibitory intracortical motor circuits. Some neurorehabilitation approaches include movement imitation training; besides the effects of motor practice, there might be a benefit due to observation and imitation of un-altered movement patterns. In this sense, virtual reality facilitates the process by customizing motor-patterns to be observed and imitated. OBJECTIVE: To evaluate the effect of a motor-imitation therapy focused on hypometria in Parkinson's disease using virtual reality. METHODS: We carried out a randomized controlled pilot-study. Sixteen patients were randomly assigned in experimental and control groups. Groups underwent 4-weeks of training based on finger-tapping with the dominant hand, in which imitation was the differential factor (only the experimental group imitated). We evaluated self-paced movement features and cortico-spinal excitability (recruitment curves and silent periods in both hemispheres) before, immediately after, and two weeks after the training period. RESULTS: Movement amplitude increased significantly after the therapy in the experimental group for the trained and un-trained hands. Motor thresholds and silent periods evaluated with transcranial magnetic stimulation were differently modified by training in the two groups; although the changes in the input-output recruitment were similar. CONCLUSIONS: This pilot study suggests that movement imitation therapy enhances the effect of motor practice in patients with Parkinson's disease; imitation-training might be helpful for reducing hypometria in these patients. These results must be clarified in future larger trials.

Cross nearest-spike interval based method to measure synchrony dynamics.

A new synchrony index for neural activity is defined in this paper. The method is able to measure synchrony dynamics in low firing rate scenarios. It is based on the computation of the time intervals between nearest spikes of two given spike trains. Generalized additive models are proposed for the synchrony profiles obtained by this method. Two hypothesis tests are proposed to assess for differences in the level of synchronization in a real data example. Bootstrap methods are used to calibrate the distribution of the tests. Also, the expected synchrony due to chance is computed analytically and by simulation to assess for actual synchronization.

Balancing the excitability of M1 circuitry during movement observation without overt replication.

Although observation of a movement increases the excitability of the motor system of the observer, it does not induce a motor replica. What is the mechanism for replica suppression? We performed a series of experiments, involving a total of 66 healthy humans, to explore the excitability of different M1 circuits and the spinal cord during observation of simple movements. Several strategies were used. In the first and second experimental blocks, we used several delay times from movement onset to evaluate the time-course modulation of the cortico-spinal excitability (CSE), and its potential dependency on the duration of the movement observed; in order to do this single pulse transcranial magnetic stimulation (TMS) over M1 was used. In subsequent experiments, at selected delay times from movement-onset, we probed the excitability of the cortico-spinal circuits using three different approaches: (i) electric cervicomedullary stimulation (CMS), to test spinal excitability, (ii) paired-pulse TMS over M1, to evaluate the cortical inhibitory-excitatory balance (short intracortical inhibition (SICI) and intracortical facilitation (ICF)], and (iii) continuous theta-burst stimulation (cTBS), to modulate the excitability of M1 cortical circuits. We observed a stereotyped response in the modulation of CSE. At 500 ms after movement-onset the ICF was increased; although the most clear-cut effect was a decrease of CSE. The compensatory mechanism was not explained by changes in SICI, but by M1-intracortical circuits targeted by cTBS. Meanwhile, the spinal cord maintained the elevated level of excitability induced when expecting to observe movements, potentially useful to facilitate any required response to the movement observed.

Motor facilitation during real-time movement imitation in Parkinson's disease: a virtual reality study.

BACKGROUND: Impaired temporal stability and poor motor unit recruitment are key impairments in Parkinsonian motor control during a whole spectrum of rhythmic movements, from simple finger tapping to gait. Therapies based on imitation can be designed for patients with motor impairments and virtual-reality (VR) offers a new perspective. Motor actions are known to depend upon the dopaminergic system, whose involvement in imitation is unknown. We sought to understand this role and the underlying possibilities for motor rehabilitation, by observing the execution of different motor-patterns during imitation in a VR environment in subjects with and without dopaminergic deficits. METHODS: 10 OFF-dose idiopathic Parkinson's Disease patients (PD), 9 age-matched and 9 young-subjects participated. Subjects performed finger-tapping at their "comfort" and "slow-comfort" rates, while immersed in VR presenting their "avatar" in 1st person perspective. Imitation was evaluated by asking subjects to replicate finger-tapping patterns different to their natural one. The finger-pattern presented matched their comfort and comfort-slow rates, but without a pause on the table (continuously moving). RESULTS: Patients were able to adapt their finger-tapping correctly, showing that in comparison with the control groups, the dopaminergic deficiency of PD did not impair imitation. During imitation the magnitude of EMG increased and the temporal variability of movement decreased. CONCLUSIONS: PD-patients have unaltered ability to imitate instructed motor-patterns, suggesting that a fully-functional dopaminergic system is not essential for such imitation. It should be further investigated if imitation training over a period of time induces positive off-line motor adaptations with transfer to non-imitation tasks.

Validity of the finger tapping test in Parkinson's disease, elderly and young healthy subjects: is there a role for central fatigue?

OBJECTIVE: The main goal of this work is to evaluate the validity of the finger tapping test (FT) to detect alterations in rhythm formation. METHODS: We use FT to study the alterations in motor rhythm in three different groups: Parkinson's patients, elderly healthy controls, and young healthy control subjects (HY). The test was performed in COMFORT and FAST tapping modes and repeated on two different days. RESULTS: For the variables analyzed (frequency and variability) both modes were repeatable in all groups. Also, intra-class correlation coefficients showed excellent levels of consistency between days. The test clearly differentiated the groups in both FAST and COMFORT modes. However, when fatigue was analyzed, a decrease in the tapping frequency was observed in HY during the FAST mode only. The amplitude of motor evoked potentials (MEPs) induced by transcranial magnetic stimulation (TMS) was early-potentiated but not delayed-depressed, both for COMFORT and FAST modes. This suggests that fatigue was not of cortico-spinal origin. Other forms of central fatigue are discussed. CONCLUSIONS: FT at FAST mode is not a valid test to detect differences in rhythm formation across the groups studied; fatigue is a confounding variable in some groups if the test is performed as fast as possible. SIGNIFICANCE: COMFORT mode is recommended in protocols including the FT for evaluating rhythm formation.