Awake ripples enhance emotional memory encoding in the human brain.

Enhanced memory for emotional experiences is hypothesized to depend on amygdala-hippocampal interactions during memory consolidation. Here we show using intracranial recordings from the human amygdala and the hippocampus during an emotional memory encoding and discrimination task increased awake ripples after encoding of emotional, compared to neutrally-valenced stimuli. Further, post-encoding ripple-locked stimulus similarity is predictive of later memory discrimination. Ripple-locked stimulus similarity appears earlier in the amygdala than in hippocampus and mutual information analysis confirms amygdala influence on hippocampal activity. Finally, the joint ripple-locked stimulus similarity in the amygdala and hippocampus is predictive of correct memory discrimination. These findings provide electrophysiological evidence that post-encoding ripples enhance memory for emotional events.

Comparing rapid rule-learning strategies in humans and monkeys.

Inter-species comparisons are key to deriving an understanding of the behavioral and neural correlates of human cognition from animal models. We perform a detailed comparison of macaque monkey and human strategies on an analogue of the Wisconsin Card Sort Test, a widely studied and applied multi-attribute measure of cognitive function, wherein performance requires the inference of a changing rule given ambiguous feedback. We found that well-trained monkeys rapidly infer rules but are three times slower than humans. Model fits to their choices revealed hidden states akin to feature-based attention in both species, and decision processes that resembled a Win-stay lose-shift strategy with key differences. Monkeys and humans test multiple rule hypotheses over a series of rule-search trials and perform inference-like computations to exclude candidates. An attention-set based learning stage categorization revealed that perseveration, random exploration and poor sensitivity to negative feedback explain the under-performance in monkeys.

A consensus statement on detection of hippocampal sharp wave ripples and differentiation from other fast oscillations.

Decades of rodent research have established the role of hippocampal sharp wave ripples (SPW-Rs) in consolidating and guiding experience. More recently, intracranial recordings in humans have suggested their role in episodic and semantic memory. Yet, common standards for recording, detection, and reporting do not exist. Here, we outline the methodological challenges involved in detecting ripple events and offer practical recommendations to improve separation from other high-frequency oscillations. We argue that shared experimental, detection, and reporting standards will provide a solid foundation for future translational discovery.

Neural computations underlying contextual processing in humans.

Context shapes our perception of facial expressions during everyday social interactions. We interpret a person's face in a hostile situation negatively and judge the same face under pleasant circumstances positively. Critical to our adaptive fitness, context provides situation-specific framing to resolve ambiguity and guide our interpersonal behavior. This context-specific modulation of facial expression is thought to engage the amygdala, hippocampus, and orbitofrontal cortex; however, the underlying neural computations remain unknown. Here we use human intracranial electroencephalograms (EEGs) directly recorded from these regions and report bidirectional theta-gamma interactions within the amygdala-hippocampal network, facilitating contextual processing. Contextual information is subsequently represented in the orbitofrontal cortex, where a theta phase shift binds context and face associations within theta cycles, endowing faces with contextual meanings at behavioral timescales. Our results identify theta phase shifts as mediating associations between context and face processing, supporting flexible social behavior.

Single-Channel EEG Based Arousal Level Estimation Using Multitaper Spectrum Estimation at Low-Power Wearable Devices.

This paper proposes a novel lightweight method using the multitaper power spectrum to estimate arousal levels at wearable devices. We show that the spectral slope (1/f) of the electrophysiological power spectrum reflects the scale-free neural activity. To evaluate the proposed feature's performance, we used scalp EEG recorded during anesthesia and sleep with technician-scored Hypnogram annotations. It is shown that the proposed methodology discriminates wakefulness from reduced arousal solely based on the neurophysiological brain state with more than 80% accuracy. Therefore, our findings describe a common electrophysiological marker that tracks reduced arousal states, which can be applied to different applications (e.g., emotion detection, driver drowsiness). Evaluation on hardware shows that the proposed methodology can be implemented for devices with a minimum RAM of 512 KB with 55 mJ average energy consumption.

Gender bias in academia: A lifetime problem that needs solutions.

Despite increased awareness of the lack of gender equity in academia and a growing number of initiatives to address issues of diversity, change is slow, and inequalities remain. A major source of inequity is gender bias, which has a substantial negative impact on the careers, work-life balance, and mental health of underrepresented groups in science. Here, we argue that gender bias is not a single problem but manifests as a collection of distinct issues that impact researchers' lives. We disentangle these facets and propose concrete solutions that can be adopted by individuals, academic institutions, and society.

Coupling between slow waves and sharp-wave ripples engages distributed neural activity during sleep in humans.

Hippocampal-dependent memory consolidation during sleep is hypothesized to depend on the synchronization of distributed neuronal ensembles, organized by the hippocampal sharp-wave ripples (SWRs, 80 to 150 Hz), subcortical/cortical slow-wave activity (SWA, 0.5 to 4 Hz), and sleep spindles (SP, 7 to 15 Hz). However, the precise role of these interactions in synchronizing subcortical/cortical neuronal activity is unclear. Here, we leverage intracranial electrophysiological recordings from the human hippocampus, amygdala, and temporal and frontal cortices to examine activity modulation and cross-regional coordination during SWRs. Hippocampal SWRs are associated with widespread modulation of high-frequency activity (HFA, 70 to 200 Hz), a measure of local neuronal activation. This peri-SWR HFA modulation is predicted by the coupling between hippocampal SWRs and local subcortical/cortical SWA or SP. Finally, local cortical SWA phase offsets and SWR amplitudes predicted functional connectivity between the frontal and temporal cortex during individual SWRs. These findings suggest a selection mechanism wherein hippocampal SWR and cortical slow-wave synchronization governs the transient engagement of distributed neuronal populations supporting hippocampal-dependent memory consolidation.

Impaired Hippocampal-Cortical Interactions during Sleep in a Mouse Model of Alzheimer's Disease.

Spatial learning is impaired in humans with preclinical Alzheimer's disease (AD). We reported similar impairments in 3xTg-AD mice learning a spatial reorientation task. Memory reactivation during sleep is critical for learning-related plasticity, and memory consolidation is correlated with hippocampal sharp wave ripple (SWR) density, cortical delta waves (DWs), cortical spindles, and the temporal coupling of these events-postulated as physiological substrates for memory consolidation. Further, hippocampal-cortical discoordination is prevalent in individuals with AD. Thus, we hypothesized that impaired memory consolidation mechanisms in hippocampal-cortical networks could account for spatial memory deficits. We assessed sleep architecture, SWR-DW dynamics, and memory reactivation in a mouse model of tauopathy and amyloidosis implanted with a recording array targeting isocortex and hippocampus. Mice underwent daily recording sessions of rest-task-rest while learning the spatial reorientation task. We assessed memory reactivation by matching activity patterns from the approach to the unmarked reward zone to patterns during slow-wave sleep (SWS). AD mice had more SWS, but reduced SWR density. The increased SWS compensated for reduced SWR density so there was no reduction in SWR number. In control mice, spindles were phase-coupled with DWs, and hippocampal SWR-cortical DW coupling was strengthened in post-task sleep and was correlated with performance on the spatial reorientation task the following day. However, in AD mice, SWR-DW and spindle-DW coupling were impaired. Thus, reduced SWR-DW coupling may cause impaired learning in AD, and spindle-DW coupling during short rest-task-rest sessions may serve as a biomarker for early AD-related changes in these brain dynamics.

Hippocampal coupling with cortical and subcortical structures in the context of memory consolidation.

Memory consolidation is a gradual process through which episodic memories become incorporated into long-term 'semantic' representations. It likely involves reactivation of neural activity encoding the recent experience during non-REM sleep. A critical prerequisite for memory consolidation is precise coordination of reactivation events between the hippocampus and cortical/subcortical structures, facilitated by the coupling of local field potential (LFP) oscillations (slow oscillations, sleep spindles and sharp wave/ripples) between these structures. We review the rapidly expanding literature on the qualitative and quantitative aspects of hippocampal oscillatory and neuronal coupling with cortical/subcortical structures in the context of memory reactivation. Reactivation in the hippocampus and cortical/subcortical structures is tightly coupled with sharp wave/ripples. Hippocampal-cortical/subcortical coupling is rich in dimensionality and this dimensionality is likely underestimated due to the limitations of the current methodology.

Laminar Organization of Encoding and Memory Reactivation in the Parietal Cortex.

Egocentric neural coding has been observed in parietal cortex (PC), but its topographical and laminar organization is not well characterized. We used multi-site recording to look for evidence of local clustering and laminar consistency of linear and angular velocity encoding in multi-neuronal spiking activity (MUA) and in the high-frequency (300-900 Hz) component of the local field potential (HF-LFP), believed to reflect local spiking activity. Rats were trained to run many trials on a large circular platform, either to LED-cued goal locations or as a spatial sequence from memory. Tuning to specific self-motion states was observed and exhibited distinct cortical depth-invariant coding properties. These patterns of collective local and laminar activation during behavior were reactivated in compressed form during post-experience sleep and temporally coupled to cortical delta waves and hippocampal sharp-wave ripples. Thus, PC neuron motion encoding is consistent across cortical laminae, and this consistency is maintained during memory reactivation.

Imaging in vivo glutamate fluctuations with [(11)C]ABP688: a GLT-1 challenge with ceftriaxone.

Molecular imaging offers unprecedented opportunities for investigating dynamic changes underlying neuropsychiatric conditions. Here, we evaluated whether [(11)C]ABP688, a positron emission tomography (PET) ligand that binds to the allosteric site of the metabotropic glutamate receptor type 5 (mGluR5), is sensitive to glutamate fluctuations after a pharmacological challenge. For this, we used ceftriaxone (CEF) administration in rats, an activator of the GLT-1 transporter (EAAT2), which is known to decrease extracellular levels of glutamate. MicroPET [(11)C]ABP688 dynamic acquisitions were conducted in rats after a venous injection of either saline (baseline) or CEF 200 mg/kg (challenge). Binding potentials (BP(ND)) were obtained using the simplified reference tissue method. Between-condition statistical parametric maps indicating brain regions showing the highest CEF effects guided placement of microdialysis probes for subsequent assessment of extracellular levels of glutamate. The CEF administration increased [(11)C]ABP688 BP(ND) in the thalamic ventral anterior (VA) nucleus bilaterally. Subsequent microdialysis assessment revealed declines in extracellular glutamate concentrations in the VA. The present results support the concept that availability of mGluR5 allosteric binding sites is sensitive to extracellular concentrations of glutamate. This interesting property of mGluR5 allosteric binding sites has potential applications for assessing the role of glutamate in the pathogenesis of neuropsychiatric conditions.

Lesions of dorsal striatum eliminate lose-switch responding but not mixed-response strategies in rats.

We used focal brain lesions in rats to examine how dorsomedial (DMS) and dorsolateral (DLS) regions of the striatum differently contribute to response adaptation driven by the delivery or omission of rewards. Rats performed a binary choice task under two modes: one in which responses were rewarded on half of the trials regardless of choice; and another 'competitive' one in which only unpredictable choices were rewarded. In both modes, control animals were more likely to use a predictable lose-switch strategy than animals with lesions of either DMS or DLS. Animals with lesions of DMS presumably relied more on DLS for behavioural control, and generated repetitive responses in the first mode. These animals then shifted to a random response strategy in the competitive mode, thereby performing better than controls or animals with DLS lesions. Analysis using computational models of reinforcement learning indicated that animals with striatal lesions, particularly of the DLS, had blunted reward sensitivity and less stochasticity in the choice mechanism. These results provide further evidence that the rodent DLS is involved in rapid response adaptation that is more sophisticated than that embodied by the classic notion of habit formation driven by gradual stimulus-response learning.

Acute NMDA receptor antagonism disrupts synchronization of action potential firing in rat prefrontal cortex.

Antagonists of N-methyl-D-aspartate receptors (NMDAR) have psychotomimetic effects in humans and are used to model schizophrenia in animals. We used high-density electrophysiological recordings to assess the effects of acute systemic injection of an NMDAR antagonist (MK-801) on ensemble neural processing in the medial prefrontal cortex of freely moving rats. Although MK-801 increased neuron firing rates and the amplitude of gamma-frequency oscillations in field potentials, the synchronization of action potential firing decreased and spike trains became more Poisson-like. This disorganization of action potential firing following MK-801 administration is consistent with changes in simulated cortical networks as the functional connections among pyramidal neurons become less clustered. Such loss of functional heterogeneity of the cortical microcircuit may disrupt information processing dependent on spike timing or the activation of discrete cortical neural ensembles, and thereby contribute to hallucinations and other features of psychosis induced by NMDAR antagonists.

Both acute and subchronic treatments with pindolol, a 5-HT(1A) and ß1 and ß2 adrenoceptor antagonist, elevate regional serotonin synthesis in the rat brain: an autoradiographic study.

Antidepressant treatments, including those that increase serotonin (5-HT) neurotransmission, require several weeks or months until the onset of the therapeutic effect in depressed patients. The negative feedback on 5-HT transmission exhibited by the 5-HT(1A) and 5-HT(1B) autoreceptors has been postulated as a possible delaying factor. The aim of the present study was to assess the effect of the acute and subchronic treatment with pindolol, a 5-HT(1A/1B,) ß1 and ß2 adrenoceptor antagonist, on 5-HT synthesis, one of the key parameters of 5-HT neurotransmission. Male Sprague-Dawley (SPD) rats (180-220 g) were treated with pindolol or an adequate volume of saline, administered either acutely (15 mg/kg i.p.; SPD-AC-SAL, SPD-AC-TR) or subchronically (15 mg/kg day i.p. for 7 days; SPD-SUBCHR-SAL, SPD-SUBCHR-TR). Thirty minutes following the single i.p. injection (acute experiment) or at the 8th day following the commencement of the subchronic treatment (subchronic experiment), 5-HT synthesis was measured using α-[¹4C]methyl-L-tryptophan autoradiography. The analysis of variance (ANOVA), followed by the Benjamini-Hochberg correction for multiple comparisons, revealed: (1) a significant increase of 5-HT synthesis in the SPD-AC-TR rats, relative to the SPD-AC-SAL rats in all brain regions examined except the substantia nigra--pars reticularis, dorsal subiculum, inferior olive, raphe magnus and raphe obscurus and (2) a significant increase of 5-HT synthesis in the SPD-SUBCHR-TR rats, relative to the SPD-SUBCHR-SAL rats in all brain regions except the median raphe, hypothalamus and raphe pontine. On the basis of these results, we hypothesized that the antagonism of the 5-HT(1A/1B) receptors prevents the negative feedback mediated by these receptors on 5-HT synthesis, resulting in a persistent increase of 5-HT synthesis. The results accord with clinical reports on the utility of pindolol in the augmentation of antidepressant treatment.

The opposite effect of a 5-HT1B receptor agonist on 5-HT synthesis, as well as its resistant counterpart, in an animal model of depression.

Flinders Sensitive Line (FSL) rat is as an animal model of depression with altered parameters of the serotonergic (5-HT) system function (5-HT synthesis rates, tissue concentrations, release, receptor density and affinity), as well as an altered sensitivity of these parameters to different 5-HT based antidepressants. The effects of acute and chronic treatments with the 5-HT(1B) agonist, CP-94253 on 5-HT synthesis, in the FSL rats and the Flinders Resistant Line (FRL) controls were measured using α-[(14)C]methyl-L-tryptophan (α-MTrp) autoradiography. CP-94253 (5mg/kg), or an adequate volume of saline, was injected i.p. as a single dose in the acute experiment or delivered via the subcutaneously implanted osmotic minipump (5 mg/kg/day for 14 days) in the chronic experiment. The acute treatment with CP-94253 significantly decreased the 5-HT synthesis in both the FRL and FSL rats, with a more widespread effect in the FRL rats. Chronic treatment with CP-94253 significantly decreased 5-HT synthesis in the FRL rats, while 5-HT synthesis in the FSL rats was significantly increased throughout the brain. In both the acute and chronic experiment, the FRL rats had higher brain 5-HT synthesis rates, relative to the FSL rats. The shift in the direction of the treatment effect from acute to chronic, using the 5-HT(1B) agonist, CP-94253, on 5-HT synthesis in the FSL model of depression, with an opposite effect on the control FRL rats, suggests the differential adaptation of the 5-HT system in the FSL and FRL rats to chronic stimulation of 5-HT(1B) receptors.

Reduced metabotropic glutamate receptor 5 in the Flinders Sensitive Line of rats, an animal model of depression: an autoradiographic study.

Depression is a brain disorder and there is still only a partial understanding of its underlying pathophysiology. Antidepressant medications with a fast onset have not yet been developed. In addition to the monoaminergic systems, the brain glutaminergic system has been implicated in the etiology of depression. Animal studies of depression have gained importance because they permit a more invasive manipulation of the subjects than human studies. In the present study, we measured the densities of the brain regional metabotropic glutaminergic receptor 5 (mGluR5) in the Flinders Sensitive Line (FSL) rat model of depression and two groups of control rats, the Flinders Resistant Line (FRL) and Sprague Dawley (SPD), the parent strain for both the FSL and FRL rats. The FSL rats showed lower densities of mGluR5 in many brain regions compared to either the SPD and/or FRL rats. In addition, the densities in the FRL rats were larger than in the SPD rats, suggesting possible problems in using FRL rats as controls. The presented data suggest that mGluR5 is lower in animal models of depression which could be related to the cognitive and emotional dysfunctions in the FSL rat model of depression and could be relevant to a better understanding of depression in humans.

Acute desipramine treatment reduces regional serotonin synthesis rates, while chronic treatment elevates rates, in a rat model of depression: an autoradiographic study.

It has been suggested that 5-HT (serotonin; 5-hydroxytryptamine) and/or the norepinephrine receptor adaptive processes in the brain are the basis for the efficacy of antidepressant treatments, including electro-convulsive shock therapy. In the present study, the effect of acute (10mg/kg; i.p. injection) and chronic (10mg/kg/day; delivered by subcutaneous mini-pump) desipramine treatments on regional 5-HT synthesis were evaluated in the Flinders Sensitive Line (FSL; "depressed" rats), as well as the control Flinders Resistant Line (FRL), of rats, using α-[(14)C]methyl-l-tryptophan autoradiography. The control rats in each of the strains received the same volume (volume in which drug was dissolved) of saline (whether through an injection or, in the case of the chronic experiments, via an osmotic mini-pump), while the treated rats received desipramine (DMI) dissolved in saline (again, as an i.p. injection or by osmotic mini-pump). The rats were randomly assigned to different groups. The results indicate that acute treatment produces a reduction in regional 5-HT synthesis in both the FSL and FRL rats, while chronic treatment produces an elevation of regional 5-HT synthesis in both strains, but the effect was somewhat greater in the FRL rats. When comparing these results to those of normal Sprague-Dawley rats, our results suggest that it is more informative to study 5-HT synthesis in an animal model of depression.

Upregulated arachidonic acid signalling in the olfactory bulbectomized rat model of depression.

The olfactory bulbectomized rat is an animal model of depression with a number of neurochemical, neuroendocrinological and behavioural features resembling human depression. Arachidonic acid (AA) is a second messenger released from the neuronal membrane phospholipids following the stimulation of the receptors coupled with G-proteins to the cytosolic phospholipase A (cPLA(2)) signalling pathway. The signalling of several neurotransmitter systems which are deregulated in OBX rats (serotonergic, dopaminergic, cholinergic, and glutamatergic) converges on the cPLA(2) signalling pathway. The aim of the present study was to assess the incorporation coefficient k* [ml/g/s] of AA in a large number of brain regions in the OBX rat, as a parameter reflecting AA turnover. Male Sprague-Dawley rats (160-200 g) were randomly assigned into an intact Sprague-Dawley (SPD) group, a Sham-operated (SHAM) group or an olfactory bulbectomized (OBX) group (n=5 per group). Two weeks following the surgeries (SHAM and OBX rats) or without any prior intervention (SPD rats), the k* was measured using [1-(14)C] AA autoradiography. Two-way ANOVA followed by the Newman-Keuls test revealed the following: (1) significantly increased AA turnover in the OBX rats, relative to the SHAM rats, in 17 out of 27 assessed brain regions; and (2) no significant differences in AA turnover between the SHAM and the SPD rats. The results suggest the upregulation of one or more neurotransmitter systems or receptors acting through the PLA(2) signalling pathway, or the components of the cPLA(2) signalling system itself. Taken together with the previous measurements, one can conclude that this elevation is likely related to upregulation in the brain serotonergic system because of the elevated 5-HT synthesis of the OBX rats.

Shift in the brain network of emotional regulation in midlife women: is the menopausal transition the turning point?

OBJECTIVE: The menopausal transition is marked by hormonal changes and is quite often accompanied by cognitive and emotional complaints. Recent data also suggest a heightened risk for depression. Little is known about the changes in emotional regulation that might contribute to the increased risk of depression in this population. The aim of this study was to examine the brain correlates of emotional regulation in healthy, nondepressed midlife women. METHODS: Functional magnetic resonance imaging was obtained in response to a standardized emotional regulation task. Levels of congruency were set and brain activation was measured during high- and low-conflict-resolution trials. RESULTS: Fourteen women aged 40 to 60 years were enrolled into the study, and 11 were included in the final analyses. Activity associated with resolution of emotional conflict was observed in the dorsolateral prefrontal cortex (P < 0.05). No regions were engaged in the generation/monitoring of emotional conflict. Moreover, there was a significant deactivation of the amygdala in response to fearful faces (P < 0.05). CONCLUSIONS: Unlike similar studies in younger populations, these results suggest a more significant engagement of the dorsolateral prefrontal cortex and less amygdala activation in emotional regulation in midlife women. These findings are, however, consistent with previous studies in older populations. We hypothesize that a shift in emotional regulation circuitry might therefore occur in women during the menopausal transition and possibly contribute to the occurrence of mood and anxiety symptoms in women during/after this period in life.