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.

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 non-human 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 likely 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.

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’.

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.

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 pointto-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.cognitive neural prosthetic | parietal reach region | area 5 D ifferent cortical areas have been identified as sources for cortical prosthetics to assist subjects with paralysis or amputation (1-13). Motor cortex can provide continuous control of trajectories (3)(4)(5)(11)(12)(13), which is consistent with its normal function of sending commands directly to the movement generating circuits of the spinal cord. More cognitive variables related to reach goals have been extracted from the parietal reach region (PRR) and area 5d in posterior parietal cortex (PPC) (7,14,15). There are several advantages of these cognitive variables for prosthetic applications: (i) decodes of goals are very fast, in the order of 100 ms, and can assist in typing applications (7); (ii) at least two sequential goals can be represented in PRR, and this feature can augment typing and sequential limb movements (16); (iii) goal and trajectory information, when combined, provide better decoding of trajectories than trajectory information alone (17); (iv) bilateral arm movements to a goal are represented and can assist in decoding bimanual behaviors from a single hemisphere (18); and (v) the anterior intraparietal area (AIP) of PPC represents grasp shape, which may reduce the number of cells needed to decode grasping (19).If PPC also encodes trajectories, then its repertoire of uses for prosthetics contr...