Patterns of theta activity in limbic anxiety circuit preceding exploratory behavior in approach-avoidance conflict

Theta oscillations within the hippocampus-amygdala-medial prefrontal cortex (HPC-AMY-mPFC) circuit have been consistently implicated in the regulation of anxiety behaviors, including risk-assessment. To study if theta activity during risk-assessment was correlated with exploratory behavior in an approach/avoidance paradigm we recorded simultaneous local field potentials from this circuit in rats exploring the elevated-plus maze (FPM). Opposing patterns of power variations in the ventral hippocampus (vHPC), basolateral amygdala (BLA), and prelimbic (PrL) mPFC, but not in the dorsal hippocampus (dHPC), during exploratory risk-assessment of the open arms preceded further exploration of the open arms or retreat back to the safer closed arms. The same patterns of theta power variations in the HPC-BLA-mPFC(PrL) circuit were also displayed by animals submitted to chronic unpredictable stress protocol known to induce an anxious state. Diverging patterns of vHPC-mPFC(PrL) theta coherence were also significantly correlated with forthcoming approach or avoidance behavior in the conflict situation in both controls and stressed animals; interestingly, vHPC-BLA, and BLA-mPFC(PrL) theta coherence correlated with future behavior only in stressed animals, underlying the pivotal role of the amygdala on the stress response.LJ was supported by fellowships: SFRH/BD/40459/2007 from the Portuguese Foundation for Science and Technology (FCT); UMINHO/BPD/27/2013 funded by CCDR-N and Programa Operational Regiao Norte (ON.2) from QREN/FEDER; and UMINHO/BPD/63/2015 from Fundacao Calouste Gulbenkian funded project (contract grant number P-139977). Financial support for this work was provided by FEDER funds through the Operational Programme Competitiveness Factors - COMPETE and National Funds through FCT under projects ECOMP-01-0124-FEDER-021145, FCT/PTDC/SAU-ENB/118383/2010, FCOMP-01-0124-FEDER-022674 and POCI-01-0145-FEDER-007038; and by the project NORTE-01-0145-FEDER-000013, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF).info:eu-repo/semantics/publishedVersio

Resolving the neural circuits of anxiety

Although anxiety disorders represent a major societal problem demanding new therapeutic targets, these efforts have languished in the absence of a mechanistic understanding of this subjective emotional state. While it is impossible to know with certainty the subjective experience of a rodent, rodent models hold promise in dissecting well-conserved limbic circuits. The application of modern approaches in neuroscience has already begun to unmask the neural circuit intricacies underlying anxiety by allowing direct examination of hypotheses drawn from existing psychological concepts. This information points toward an updated conceptual model for what neural circuit perturbations could give rise to pathological anxiety and thereby provides a roadmap for future therapeutic development.National Institute of Diabetes and Digestive and Kidney Diseases (U.S.) (NIH Director’s New Innovator Award DP2-DK-102256-01)National Institute of Mental Health (U.S.) (NIH) R01-MH102441-01)JPB Foundatio

Patterns of Coupled Theta Activity in Amygdala-Hippocampal-Prefrontal Cortical Circuits during Fear Extinction

Signals related to fear memory and extinction are processed within brain pathways involving the lateral amygdala (LA) for formation of aversive stimulus associations, the CA1 area of the hippocampus for context-dependent modulation of these associations, and the infralimbic region of the medial prefrontal cortex (mPFC) for extinction processes. While many studies have addressed the contribution of each of these modules individually, little is known about their interactions and how they function as an integrated system. Here we show, by combining multiple site local field potential (LFP) and unit recordings in freely behaving mice in a fear conditioning paradigm, that theta oscillations may provide a means for temporally and functionally connecting these modules. Theta oscillations occurred with high specificity in the CA1-LA-mPFC network. Theta coupling increased between all areas during retrieval of conditioned fear, and declined during extinction learning. During extinction recall, theta coupling partly rebounded in LA-mPFC and CA1-mPFC, and remained at a low level in CA1-LA. Interfering with theta coupling through local electrical microstimulation in CA1-LA affected conditioned fear and extinction recall depending on theta phase. These results support the hypothesis that theta coupling provides a means for inter-areal coordination in conditioned behavioral responsiveness. More specifically, theta oscillations seem to contribute to a population code indicating conditioned stimuli during recall of fear memory before and after extinction

Environmental enrichment has no effect on the development of dopaminergic and GABAergic fibers during methylphenidate treatment of early traumatized gerbils

It is widely believed, that environmental factors play a crucial role in the etiology and outcome of psychiatric diseases such as Attention-Deficit/Hyperactivity Disorder (ADHD). A former study from our laboratory has shown that both methylphenidate (MP) and handling have a positive effect on the dopaminergic fiber density in the prefrontal cortex (PFC) of early traumatized gerbils (Meriones unguiculatus). The current study was performed to investigate if enriched environment during MP application has an additional influence on the dopaminergic and GABAergic fiber densities in the PFC and amygdala in this animal model

Spike-Timing Precision and Neuronal Synchrony Are Enhanced by an Interaction between Synaptic Inhibition and Membrane Oscillations in the Amygdala

The basolateral complex of the amygdala (BLA) is a critical component of the neural circuit regulating fear learning. During fear learning and recall, the amygdala and other brain regions, including the hippocampus and prefrontal cortex, exhibit phase-locked oscillations in the high delta/low theta frequency band (∼2–6 Hz) that have been shown to contribute to the learning process. Network oscillations are commonly generated by inhibitory synaptic input that coordinates action potentials in groups of neurons. In the rat BLA, principal neurons spontaneously receive synchronized, inhibitory input in the form of compound, rhythmic, inhibitory postsynaptic potentials (IPSPs), likely originating from burst-firing parvalbumin interneurons. Here we investigated the role of compound IPSPs in the rat and rhesus macaque BLA in regulating action potential synchrony and spike-timing precision. Furthermore, because principal neurons exhibit intrinsic oscillatory properties and resonance between 4 and 5 Hz, in the same frequency band observed during fear, we investigated whether compound IPSPs and intrinsic oscillations interact to promote rhythmic activity in the BLA at this frequency. Using whole-cell patch clamp in brain slices, we demonstrate that compound IPSPs, which occur spontaneously and are synchronized across principal neurons in both the rat and primate BLA, significantly improve spike-timing precision in BLA principal neurons for a window of ∼300 ms following each IPSP. We also show that compound IPSPs coordinate the firing of pairs of BLA principal neurons, and significantly improve spike synchrony for a window of ∼130 ms. Compound IPSPs enhance a 5 Hz calcium-dependent membrane potential oscillation (MPO) in these neurons, likely contributing to the improvement in spike-timing precision and synchronization of spiking. Activation of the cAMP-PKA signaling cascade enhanced the MPO, and inhibition of this cascade blocked the MPO. We discuss these results in the context of spike-timing dependent plasticity and modulation by neurotransmitters important for fear learning, such as dopamine

Ontogeny of the dopamine innervation in the nucleus accumbens of gerbils

Lesting J, Neddens J, Teuchert-Noodt G. Ontogeny of the dopamine innervation in the nucleus accumbens of gerbils. BRAIN RESEARCH. 2005;1066(1-2):16-23.The postnatal maturation of immunohistochemically stained dopamine (DA) fibres was quantitatively examined in the core and shell subareas of the nucleus accumbens (NAC) of gerbils. Animals of different ages, ranging from juvenile [postnatal day (PD) 14, 30] to adolescent (PD70), adult (PD90, PD180, PD360) and ageing (PD540, PD720) were analysed. The timescale of the maturation of the accumbal DA innervation was regionally different, probably due to the different origin of DA fibres in the mesencephalon. Both the accumbal core, with DA afferents arising from the lateral ventral tegmental area (VTA) and the substantia nigra pars compacta, as well as the accumbal shell, with DA afferents arising from the medial VTA, show moderate DA fibre densities at PD14. The core displayed a significant decrease of the DA fibre density up to PD30 and a subsequent significant increase between PD70 and 90, whereas the shell solely showed an augmentation of the DA innervation between PD70 and 90. Our data suggest that the different maturation of the DA innervation in core and shell might reflect differences in the development of motor and limbic functions, mediated by the nigrostriate and the mesolimbic system, respectively. (c) 2005 Published by Elsevier B.V

Serotonin fibre densities in, subcortical areas: differential effects of isolated rearing and methamphetamine

Lehmann K, Lesting J, Polascheck D, Teuchert-Noodt G. Serotonin fibre densities in, subcortical areas: differential effects of isolated rearing and methamphetamine. DEVELOPMENTAL BRAIN RESEARCH. 2003;147(1-2):143-152.Serotoninergic neurons interact with dopaminergic cells on all levels and are physiologically affected by both isolated rearing (IR) and a single early methamphetamine (MA) injection. We therefore checked for anatomical effects of both interventions by immunohistochemically staining serotonin fibres and assessing fibre densities in the caudate-putamen (CPu), nucleus accumbens (NAc) and amygdala of Mongolian gerbils. IR led to significantly increased 5-HT fibre densities in the dorsal part of the CPu and in the central and basolateral amygdala. No effects were seen in the ventral CPu, in the NAc and in the lateral amygdala. The early MA injection resulted in a denser 5-HT innervation in the dorsomedial and ventromedial CPu, in the NAc shell of animals reared in an enriched environment and in the NAc core of both rearing conditions, leaving the lateral CPu and the amygdala unaffected. Thus, the single pharmacological versus the environmental challenge exerts an almost complementary effect on the 5-HT innervation in different areas of the brain, which demonstrates that systemic interactions, e.g. with dopaminergic and glutamatergic afferents, must be taken into account when the seemingly uniform 5-HT projections are investigated. (C) 2003 Elsevier B.V. All rights reserved

Hemisphere-specific effects on serotonin but not dopamine innervation in the nucleus accumbens of gerbils caused by isolated rearing and a single early methamphetamine challenge

Lesting J, Neddens J, Busche A, Teuchert-Noodt G. Hemisphere-specific effects on serotonin but not dopamine innervation in the nucleus accumbens of gerbils caused by isolated rearing and a single early methamphetamine challenge. BRAIN RESEARCH. 2005;1035(2):168-176.The aim of this study was twofold: We examined whether serotonin (5-HT) and dopamine (DA) innervations of the nucleus accumbens are lateralised and whether the environment or the combination with an early pharmacological impact might interfere with the postnatal maturation of the monoaminergic innervation. Male gerbils were assigned to either enriched rearing (ER) or isolated rearing (IR). Animals from both rearing conditions additionally received a single dose of either methamphetamine [MA (50 mg/kg ip)] or saline on postnatal day 14. DA and 5-HT fibres of the adult animals (postnatal day 90-110) were immunocytochemically stained and fibre densities were quantified in nucleus accumbens core and shell of both the left and right hemisphere. Our data demonstrate that the DA and 5-HT innervation is not lateralised in saline-treated animals of both rearing conditions. IR increases the DA fibre density in both hemispheres of saline controls, whereas an additional MA treatment reverses this effect. In both ER and IR groups, MA provokes an excessive 5-HT fibre in growth of only the right hemisphere. The combination of IR with MA induces right-side asymmetries of the 5-HT fibre density in both the core and shell. From the data obtained, we conclude that the maturation of the monoaminergic innervation of the nucleus accumbens is vulnerable to postnatal stimuli. The subtle "innervation imbalance" observed in our studies is consistent with previously reported effects in other brain regions of this animal model and may be causative for behavioural disturbances. (c) 2005 Elsevier B.V. All rights reserved

Impaired extinction of fear and maintained amygdala-hippocampal theta synchrony in a mouse model of temporal lobe epilepsy

Purpose:  The relationship between epilepsy and fear has received much attention. However, seizure-modulated fear and physiologic or structural correlates have not been examined systematically, and the underlying basics of network levels remain unclear to date. Therefore, this project was set up to characterize the neurophysiologic basis of seizure-related fear and the contribution of the amygdala-hippocampus system. Methods:  The experimental strategy was composed of the following steps: (1) use of the mouse pilocarpine model of temporal lobe epilepsy (TLE); (2) behavioral analyses of anxiety states in the elevated plus maze test, light–dark avoidance test, and Pavlovian fear conditioning; and (3) probing neurophysiologic activity patterns in amygdala-hippocampal circuits in freely behaving mice. Results:  Our results displayed no significant differences in basic anxiety levels comparing mice that developed spontaneous recurrent seizures (SRS) and controls. Furthermore, conditioned fear memory retrieval was not influenced in SRS mice. However, during fear memory extinction, SRS mice showed an extended freezing behavior and a maintained amygdala-hippocampal theta frequency synchronization compared to controls. Discussion:  These results indicate specific alterations in conditioned fear behavior and related neurophysiologic activities in the amygdala-hippocampal network contributing to impaired fear memory extinction in mice with TLE. Clinically, the nonextinguished fear memories may well contribute to the experience of fear in patients with TLE