Structural and Functional Remodeling of Amygdala GABAergic Synapses in Associative Fear Learning.

Associative learning is thought to involve different forms of activity-dependent synaptic plasticity. Although previous studies have mostly focused on learning-related changes occurring at excitatory glutamatergic synapses, we found that associative learning, such as fear conditioning, also entails long-lasting functional and structural plasticity of GABAergic synapses onto pyramidal neurons of the murine basal amygdala. Fear conditioning-mediated structural remodeling of GABAergic synapses was associated with a change in mIPSC kinetics and an increase in the fraction of synaptic benzodiazepine-sensitive (BZD) GABAA receptors containing the α2 subunit without altering the intrasynaptic distribution and overall amount of BZD-GABAA receptors. These structural and functional synaptic changes were partly reversed by extinction training. These findings provide evidence that associative learning, such as Pavlovian fear conditioning and extinction, sculpts inhibitory synapses to regulate inhibition of active neuronal networks, a process that may tune amygdala circuit responses to threats.

Spatial and temporal eye-hand coordination relies on the parietal reach region.

Coordinated eye movements are crucial for precision control of our hands. A commonly believed neural mechanism underlying eye-hand coordination is interaction between the neural networks controlling each effector, exchanging, and matching information, such as movement target location and onset time. Alternatively, eye-hand coordination may result simply from common inputs to independent eye and hand control pathways. Thus far, it remains unknown whether and where either of these two possible mechanisms exists. A candidate location for the former mechanism, interpathway communication, includes the posterior parietal cortex (PPC) where distinct effector-specific areas reside. If the PPC were within the network for eye-hand coordination, perturbing it would affect both eye and hand movements that are concurrently planned. In contrast, if eye-hand coordination arises solely from common inputs, perturbing one effector pathway, e.g., the parietal reach region (PRR), would not affect the other effector. To test these hypotheses, we inactivated part of PRR in the macaque, located in the medial bank of the intraparietal sulcus encompassing the medial intraparietal area and area 5V. When each effector moved alone, PRR inactivation shortened reach but not saccade amplitudes, compatible with the known reach-selective activity of PRR. However, when both effectors moved concurrently, PRR inactivation shortened both reach and saccade amplitudes, and decoupled their reaction times. Therefore, consistent with the interpathway communication hypothesis, we propose that the planning of concurrent eye and hand movements causes the spatial information in PRR to influence the otherwise independent eye control pathways, and that their temporal coupling requires an intact PRR.

Optic ataxia: from Balint's syndrome to the parietal reach region.

Optic ataxia is a high-order deficit in reaching to visual goals that occurs with posterior parietal cortex (PPC) lesions. It is a component of Balint's syndrome that also includes attentional and gaze disorders. Aspects of optic ataxia are misreaching in the contralesional visual field, difficulty preshaping the hand for grasping, and an inability to correct reaches online. Recent research in nonhuman primates (NHPs) suggests that many aspects of Balint's syndrome and optic ataxia are a result of damage to specific functional modules for reaching, saccades, grasp, attention, and state estimation. The deficits from large lesions in humans are probably composite effects from damage to combinations of these functional modules. Interactions between these modules, either within posterior parietal cortex or downstream within frontal cortex, may account for more complex behaviors such as hand-eye coordination and reach-to-grasp.

Deep brain stimulation, histone deacetylase inhibitors and glutamatergic drugs rescue resistance to fear extinction in a genetic mouse model.

Anxiety disorders are characterized by persistent, excessive fear. Therapeutic interventions that reverse deficits in fear extinction represent a tractable approach to treating these disorders. We previously reported that 129S1/SvImJ (S1) mice show no extinction learning following normal fear conditioning. We now demonstrate that weak fear conditioning does permit fear reduction during massed extinction training in S1 mice, but reveals specific deficiency in extinction memory consolidation/retrieval. Rescue of this impaired extinction consolidation/retrieval was achieved with d-cycloserine (N-methly-d-aspartate partial agonist) or MS-275 (histone deacetylase (HDAC) inhibitor), applied after extinction training. We next examined the ability of different drugs and non-pharmacological manipulations to rescue the extreme fear extinction deficit in S1 following normal fear conditioning with the ultimate aim to produce low fear levels in extinction retrieval tests. Results showed that deep brain stimulation (DBS) by applying high frequency stimulation to the nucleus accumbens (ventral striatum) during extinction training, indeed significantly reduced fear during extinction retrieval compared to sham stimulation controls. Rescue of both impaired extinction acquisition and deficient extinction consolidation/retrieval was achieved with prior extinction training administration of valproic acid (a GABAergic enhancer and HDAC inhibitor) or AMN082 [metabotropic glutamate receptor 7 (mGlu7) agonist], while MS-275 or PEPA (AMPA receptor potentiator) failed to affect extinction acquisition in S1 mice. Collectively, these data identify potential beneficial effects of DBS and various drug treatments, including those with HDAC inhibiting or mGlu7 agonism properties, as adjuncts to overcome treatment resistance in exposure-based therapies. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Inactivation of the parietal reach region causes optic ataxia, impairing reaches but not saccades.

Lesions in human posterior parietal cortex can cause optic ataxia (OA), in which reaches but not saccades to visual objects are impaired, suggesting separate visuomotor pathways for the two effectors. In monkeys, one potentially crucial area for reach control is the parietal reach region (PRR), in which neurons respond preferentially during reach planning as compared to saccade planning. However, direct causal evidence linking the monkey PRR to the deficits observed in OA is missing. We thus inactivated part of the macaque PRR, in the medial wall of the intraparietal sulcus, and produced the hallmarks of OA, misreaching for peripheral targets but unimpaired saccades. Furthermore, reach errors were larger for the targets preferred by the neural population local to the injection site. These results demonstrate that PRR is causally involved in reach-specific visuomotor pathways, and reach goal disruption in PRR can be a neural basis of OA.

Cognitive signals for brain-machine interfaces in posterior parietal cortex include continuous 3D trajectory commands.

Cortical neural prosthetics extract command signals from the brain with the goal to restore function in paralyzed or amputated patients. Continuous control signals can be extracted from the motor cortical areas, whereas neural activity from posterior parietal cortex (PPC) can be used to decode cognitive variables related to the goals of movement. Because typical activities of daily living comprise both continuous control tasks such as reaching, and tasks benefiting from discrete control such as typing on a keyboard, availability of both signals simultaneously would promise significant increases in performance and versatility. Here, we show that PPC can provide 3D hand trajectory information under natural conditions that would be encountered for prosthetic applications, thus allowing simultaneous extraction of continuous and discrete signals without requiring multisite surgical implants. We found that limb movements can be decoded robustly and with high accuracy from a small population of neural units under free gaze in a complex 3D point-to-point reaching task. Both animals' brain-control performance improved rapidly with practice, resulting in faster target acquisition and increasing accuracy. These findings disprove the notion that the motor cortical areas are the only candidate areas for continuous prosthetic command signals and, rather, suggests that PPC can provide equally useful trajectory signals in addition to discrete, cognitive variables. Hybrid use of continuous and discrete signals from PPC may enable a new generation of neural prostheses providing superior performance and additional flexibility in addressing individual patient needs.

Enhanced fear expression in a psychopathological mouse model of trait anxiety: pharmacological interventions.

The propensity to develop an anxiety disorder is thought to be determined by genetic and environmental factors. Here we investigated the relationship between a genetic predisposition to trait anxiety and experience-based learned fear in a psychopathological mouse model. Male CD-1 mice selectively bred for either high (HAB), or normal (NAB) anxiety-related behaviour on the elevated plus maze were subjected to classical fear conditioning. During conditioning both mouse lines showed increased fear responses as assessed by freezing behaviour. However, 24 h later, HAB mice displayed more pronounced conditioned responses to both a contextual or cued stimulus when compared with NAB mice. Interestingly, 6 h and already 1 h after fear conditioning, freezing levels were high in HAB mice but not in NAB mice. These results suggest that trait anxiety determines stronger fear memory and/or a weaker ability to inhibit fear responses in the HAB line. The enhanced fear response of HAB mice was attenuated by treatment with either the α(2,3,5)-subunit selective benzodiazepine partial agonist L-838,417, corticosterone or the selective neurokinin-1 receptor antagonist L-822,429. Overall, the HAB mouse line may represent an interesting model (i) for identifying biological factors underlying misguided conditioned fear responses and (ii) for studying novel anxiolytic pharmacotherapies for patients with fear-associated disorders, including post-traumatic stress disorder and phobias.

Rescue of impaired fear extinction and normalization of cortico-amygdala circuit dysfunction in a genetic mouse model by dietary zinc restriction.

Fear extinction is impaired in neuropsychiatric disorders, including posttraumatic stress disorder. Identifying drugs that facilitate fear extinction in animal models provides leads for novel pharmacological treatments for these disorders. Zinc (Zn) is expressed in neurons in a cortico-amygdala circuit mediating fear extinction, and modulates neurotransmitter systems regulating extinction. We previously found that the 129S1/SvImJ mouse strain (S1) exhibited a profound impairment in fear extinction, coupled with abnormalities in the activation of the extinction circuit. Here, we tested the role of Zn in fear extinction in S1 and C57BL/6N reference strain (B6) by feeding the mice a Zn-restricted diet (ZnR) and testing for fear extinction, as well as neuronal activation of the extinction circuit via quantification of the immediate-early genes c-Fos and Zif268. Results showed that (preconditioning or postconditioning) ZnR completely rescued deficient extinction learning and long-term extinction retrieval in S1 and expedited extinction learning in B6, without affecting fear acquisition or fear expression. The extinction-facilitating effects of ZnR were associated with the normalization of Zif268 and/or c-Fos expression in cortico-amygdala regions of S1. Specifically, ZnR increased activity in infralimbic cortex, lateral and basolateral amygdala nuclei, and lateral central amygdala nucleus, and decreased activity in prelimbic and insular cortices and medial central amygdala nucleus. ZnR also increased activation in the main intercalated nucleus and decreased activation of the medial paracapsular intercalated mass in S1. Our findings reveal a novel role for Zn in fear extinction and further support the utility of the S1 model for identifying extinction facilitating drugs.

Impaired extinction of learned fear in rats selectively bred for high anxiety--evidence of altered neuronal processing in prefrontal-amygdala pathways.

The impaired extinction of acquired fear is a core symptom of anxiety disorders, such as post-traumatic stress disorder, phobias or panic disorder, and is known to be particularly resistant to existing pharmacotherapy. We provide here evidence that a similar relationship between trait anxiety and resistance to extinction of fear memory can be mimicked in a psychopathologic animal model. Wistar rat lines selectively bred for high (HAB) or low (LAB) anxiety-related behaviour were tested in a classical cued fear conditioning task utilizing freezing responses as a measure of fear. Fear acquisition was similar in both lines. In the extinction trial, however, HAB rats showed a marked deficit in the attenuation of freezing responses to repeated auditory conditioned stimulus presentations as compared with LAB rats, which exhibited rapid extinction. To gain information concerning the putatively altered neuronal processing associated with the differential behavioural response between HAB and LAB rats, c-Fos expression was investigated in the main prefrontal-amygdala pathways important for cued fear extinction. HAB compared to LAB rats showed an attenuated c-Fos response to repeated conditioned stimulus presentations in infralimbic and cingulate cortices, as well as in the lateral amygdala, but facilitated the c-Fos response in the medial part of the central amygdala. In conclusion, the present results support the notion that impaired extinction in high anxiety rats is accompanied by an aberrant activation profile in extinction-relevant prefrontal-amygdala circuits. Thus, HAB rats may represent a clinically relevant model to study the mechanisms and potential targets to accelerate delayed extinction processes in subjects with enhanced trait anxiety.

A real-time virtual integration environment for the design and development of neural prosthetic systems.

We have developed a virtual integration environment (VIE) for the development of neural prosthetic systems. The VIE is a software environment that modularizes the core functions of a neural prosthetic system--receiving signals, decoding signals and controlling a real or simulated device. Complete prosthetic systems can be quickly assembled by linking pre-existing modules together through standard interfaces. Systems can be simulated in real-time, and simulated components can be swapped out for real hardware. This paper is the first of two companion papers that describe the VIE and its use. In this paper, we first describe the architecture of the VIE and review implemented modules. We then describe the use of the VIE for the real-time validation of neural decode algorithms from pre-recorded data, the use of the VIE in closed loop primate experiments and the use of the VIE in the clinic.

Model-based development of neural prostheses for movement.

Neural prostheses for restoration of limb movement in paralyzed and amputee patients tend to be complex systems. Subjective intuition and trial-and-error approaches have been applied to the design and clinical fitting of simple systems with limited functionality. These approaches are time consuming, difficult to apply in larger scale, and not applicable to limbs under development with more anthropomorphic motion and actuation. The field of neural prosthetics is in need of more systematic methods, including tools that will allow users to develop accurate models of neural prostheses and simulate their behavior under various conditions before actual manufacturing or clinical application. Such virtual prototyping would provide an efficient and safe test-bed for narrowing the design choices and tuning the control parameters before actual clinical application. We describe a software environment that we have developed to facilitate the construction and modification of accurate mathematical models of paralyzed and prosthetic limbs and simulate their movement under various neural control strategies. These simulations can be run in real time with a stereoscopic display to enable design engineers and prospective users to evaluate a candidate neural prosthetic system and learn to operate it before actually receiving it.

A virtual reality environment for designing and fitting neural prosthetic limbs.

Building and testing novel prosthetic limbs and control algorithms for functional electrical stimulation (FES) is expensive and risky. Here, we describe a virtual reality environment (VRE) to facilitate and accelerate the development of novel systems. In the VRE, subjects/patients can operate a simulated limb to interact with virtual objects. Realistic models of all relevant musculoskeletal and mechatronic components allow the development of entire prosthetic systems in VR before introducing them to the patient. The system is used both by engineers as a development tool and by clinicians to fit prosthetic devices to patients.