Effects of vagus nerve stimulation on extinction of conditioned fear and post-traumatic stress disorder symptoms in rats.

Exposure-based therapies help patients with post-traumatic stress disorder (PTSD) to extinguish conditioned fear of trauma reminders. However, controlled laboratory studies indicate that PTSD patients do not extinguish conditioned fear as well as healthy controls, and exposure therapy has high failure and dropout rates. The present study examined whether vagus nerve stimulation (VNS) augments extinction of conditioned fear and attenuates PTSD-like symptoms in an animal model of PTSD. To model PTSD, rats were subjected to a single prolonged stress (SPS) protocol, which consisted of restraint, forced swim, loss of consciousness, and 1 week of social isolation. Like PTSD patients, rats subjected to SPS show impaired extinction of conditioned fear. The SPS procedure was followed, 1 week later, by auditory fear conditioning (AFC) and extinction. VNS or sham stimulation was administered during half of the extinction days, and was paired with presentations of the conditioned stimulus. One week after completion of extinction training, rats were given a battery of behavioral tests to assess anxiety, arousal and avoidance. Results indicated that rats given SPS 1 week prior to AFC (PTSD model) failed to extinguish the freezing response after eleven consecutive days of extinction. Administration of VNS reversed the extinction impairment and attenuated reinstatement of the conditioned fear response. Delivery of VNS during extinction also eliminated the PTSD-like symptoms, such as anxiety, hyperarousal and social avoidance for more than 1 week after VNS treatment. These results provide evidence that extinction paired with VNS treatment can lead to remission of fear and improvements in PTSD-like symptoms. Taken together, these findings suggest that VNS may be an effective adjunct to exposure therapy for the treatment of PTSD.

Detection and identification of speech sounds using cortical activity patterns.

We have developed a classifier capable of locating and identifying speech sounds using activity from rat auditory cortex with an accuracy equivalent to behavioral performance and without the need to specify the onset time of the speech sounds. This classifier can identify speech sounds from a large speech set within 40 ms of stimulus presentation. To compare the temporal limits of the classifier to behavior, we developed a novel task that requires rats to identify individual consonant sounds from a stream of distracter consonants. The classifier successfully predicted the ability of rats to accurately identify speech sounds for syllable presentation rates up to 10 syllables per second (up to 17.9 ± 1.5 bits/s), which is comparable to human performance. Our results demonstrate that the spatiotemporal patterns generated in primary auditory cortex can be used to quickly and accurately identify consonant sounds from a continuous speech stream without prior knowledge of the stimulus onset times. Improved understanding of the neural mechanisms that support robust speech processing in difficult listening conditions could improve the identification and treatment of a variety of speech-processing disorders.

Vagus nerve stimulation during rehabilitative training improves forelimb strength following ischemic stroke.

Upper limb impairment is a common debilitating consequence of ischemic stroke. Physical rehabilitation after stroke enhances neuroplasticity and improves limb function, but does not typically restore normal movement. We have recently developed a novel method that uses vagus nerve stimulation (VNS) paired with forelimb movements to drive specific, long-lasting map plasticity in rat primary motor cortex. Here we report that VNS paired with rehabilitative training can enhance recovery of forelimb force generation following infarction of primary motor cortex in rats. Quantitative measures of forelimb function returned to pre-lesion levels when VNS was delivered during rehab training. Intensive rehab training without VNS failed to restore function back to pre-lesion levels. Animals that received VNS during rehab improved twice as much as rats that received the same rehabilitation without VNS. VNS delivered during physical rehabilitation represents a novel method that may provide long-lasting benefits towards stroke recovery.

Fear conditioning alters neuron-specific hippocampal place field stability via the basolateral amygdala.

It is well established that physical changes to an environment result in plasticity of hippocampal place cell activity, while in the absence of changes, place fields are remarkably stable. Manipulations of a rat's perception of the environment without physically changing the environment also result in plasticity of place cell firing. Here, we tested the hypothesis that a rat's perception of an environment could be changed by introducing an auditory fear-conditioned stimulus (CS) to a previously neutral environment, inducing plasticity of hippocampal place fields. First, stable place fields were isolated for rats exploring a radial-arm maze in one environment, and then the rats were fear-conditioned to an auditory CS in a completely separate environment. Later, the CS was specifically paired once with a location in the previously neutral radial-arm maze, either within the given neuron's place field (in-field) or an area outside of the place field (out-of-field). A single, paired presentation of the CS with a location in-field for a specific place cell disrupted the stability of that neuron's place field, whereas pairing the CS with a location out-of-field did not affect place field stability. We further showed that this place field disruption for a CS presented in-field was mediated by inputs from the basolateral amygdala (BLA). Temporarily inactivating the BLA immediately post-CS re-exposure attenuated the CS-induced place field destabilization. Our results show neuron-specific conditional plasticity for actively firing hippocampal place cells, and that the BLA mediates this plasticity when an emotionally arousing or fear-related CS is used.

Complex mixture discrimination and the role of contaminants.

Rats were trained in a 2-alternative odor choice task to discriminate between a 10-component odor mixture and the same mixture with one component removed and replaced with 1 of 3 concentrations of a different monomolecular odor (contaminant). All stimuli were presented within a training session, thus the rat essentially had to learn to discriminate the 10-component mixture from "not" the 10-component mixture. Rats performed most poorly discriminating the complete mixture from the mixture with one component removed and no contaminant added. As the concentration of the contaminant increased from 10 ppm to a concentration equal to the other components (100 ppm), discrimination improved linearly. In analyses of individual differences, rats that spent more time in the sampling port (sampling and making a decision) were more accurate than rats that spent less time. Together, these results emphasize the balance between perceptual stability and perceptual discrimination expressed by the olfactory system dealing with dynamic mixtures and the robust effects of contamination on those processes. In addition, they provide further support that modification of sampling/decision time is a strategy used by rats to deal with difficult discriminations of complex odors.

Minocycline increases quality and longevity of chronic neural recordings.

Brain/machine interfaces could potentially be used in the treatment of a host of neurological disorders ranging from paralysis to sensory deficits. Insertion of chronic micro-electrode arrays into neural tissue initiates a host of immunological responses, which typically leads to the formation of a cellular sheath around the implant, resulting in the loss of useful signals. Minocycline has been shown to have neuroprotective and neurorestorative effects in certain neural injury and neurodegenerative disease models. This study examined the effects of minocycline administration on the quality and longevity of chronic multi-channel microwire neural implants 1 week and 1 month post-implantation in auditory cortex. The mean signal-to-noise ratio for the minocycline group stabilized at the end of week 1 and remained above 4.6 throughout the following 3 weeks. The control group signal-to-noise ratio dropped throughout the duration of the study and at the end of 4 weeks was 2.6. Furthermore, 68% of electrodes from the minocycline group showed significant stimulus-driven activity at week 4 compared to 12.5% of electrodes in the control group. There was a significant reduction in the number of activated astrocytes around the implant in minocycline subjects, as well as a reduction in total area occupied by activated astrocytes at 1 and 4 weeks.

Anesthesia suppresses nonsynchronous responses to repetitive broadband stimuli.

Although many aspects of sensory processing are qualitatively similar in awake and anesthetized subjects, important state-dependent differences are known to exist. To investigate the effects of anesthesia on temporal processing in rat auditory cortex, multi-unit neural responses to trains of broadband clicks were recorded prior to, 15 min following, and 5 h following the administration of a ketamine-based anesthetic. While responses to clicks in isolation were relatively stable between states, responses to subsequent clicks exhibited increases in latency, peak latency, response duration, and post-onset suppression under anesthesia. Ketamine anesthetic reduced the maximum rate at which multi-unit clusters entrained to repeated clicks. No multi-unit clusters entrained to stimulus presentation rates greater than 33 Hz under anesthesia, compared with 85% and 81% in the pre- and post-anesthetic condition, respectively. Anesthesia also induced oscillatory activity that was not present in awake subjects. Finally, ketamine anesthesia abolished all tonic excitatory and suppressive nonsynchronous responses to click trains. The results of this study suggest that ketamine-based anesthesia significantly alters neural coding of broadband click trains in auditory cortex.

Response to broadband repetitive stimuli in auditory cortex of the unanesthetized rat.

This study examines the ability of multi-unit clusters (MUCs) in layer IV/V of primary auditory cortex of the awake rat to respond to a series of broadband click trains. The data from 113 multi-unit clusters were analyzed for synchronous and nonsynchronized responses using several methods. Synchronous responses were measured using window analysis, circular statistics and spectral analysis. Nonsynchronous responses were measured during different time intervals during the click train (first 50 ms, 50-450 ms, and the entire click train). The results demonstrate that multi-unit clusters are capable of synchronizing to clicks at rates up to 166 Hz. The mean synchronization boundary (limiting rate) for the group was found to be 72 Hz. Mean peak response rate, mean response duration, and mean time-to-peak response decreased as the stimulus presentation rate (SPR) increased, resulting in a temporal sharpening of the population response. For fast SPRs (>50 Hz), 50% of MUCs exhibited nonsynchronous responses in which the firing rate increased with SPR, although this activity was most prevalent during the first 50 ms of the response. Sustained increases in firing rate with SPR were seen in 8% of the MUCs, while another 38% of MUCs exhibited sustained decreases during the click train.

A comparison of chronic multi-channel cortical implantation techniques: manual versus mechanical insertion.

High-density multi-channel intra-cortical electrode arrays allow researchers to record simultaneously from populations of neurons for the purpose of understanding neural coding and plasticity. These devices have tens to hundreds of electrodes spaced within a few square millimeters. During insertion, the high-density probes can compress the cortex several millimeters prior to breaking through the pia. Compression of cortical tissue has been demonstrated to result in traumatic brain injury (TBI) which may be a major contributor to low electrode yield and decreased recording longevity. Two insertion techniques for chronically implanting multi-wire electrode arrays in layer IV of primary auditory cortex were compared. A mechanical insertion device, capable of rapidly inserting the electrode array without visible compression of the brain, was constructed. The neural responses to broadband clicks and pure tones recorded from the arrays inserted with the mechanical device were compared to the results from a manual insertion method using a micromanipulator. Both techniques result in a similar number of active channels directly following surgery with a mean signal-to-noise ratio of approximately 4.5. Over 60% of the animals implanted with the mechanical insertion device had driven activity at week 6 whereas none of the animals with manually inserted arrays exhibited functional responses after 3 weeks. This report provides initial evidence that mechanical insertion devices, which prevent cortical compression, increase electrode recording longevity.

An economical multi-channel cortical electrode array for extended periods of recording during behavior.

We report the development of a low-cost chronic multi-channel microwire electrode array for recording multi-unit cortical responses in behaving rodents. The design was motivated by three issues. First, standard connector systems tended to disconnect from the head-stage during extended periods of behavior. Disconnections resulted in a loss of data and an interruption of the animals' behavior. Second, the use of low insertion force connectors with locking mechanisms was cost prohibitive. Finally, connecting the head-stage to a skull-mounted connector on an unrestrained animal was highly stressful for both the researcher and animal. The design developed uses a high insertion force DIP socket separated from the skullcap that prevents inadvertent disconnects, is inexpensive, and simplifies connecting unrestrained rodents. Electrodes were implanted in layer IV of primary auditory cortex in 11 Sprague-Dawley rats. Performance of the electrodes was monitored for 6 weeks. None of the behaving animals became disconnected from the recording system during recording sessions lasting 6 h. The mean signal-to-noise ratio on all channels (154) following surgery was 3.9+/-0.2. Of the 154 channels implanted, 130 exhibited driven activity following surgery. Forty percent of the arrays continued to exhibit driven neural activity at 6 weeks.

Long-term neural recording characteristics of wire microelectrode arrays implanted in cerebral cortex.

This paper describes a detailed protocol for obtaining chronic, multi-site unit recordings in cerebral cortex of awake animals for periods of three months or more. The protocol includes details for making relatively simple and inexpensive implantable multichannel electrodes that consist of arrays of separate microwires. The results reported in this paper suggest that a viable implant will have discriminable unit activity on about 80% of the electrodes, resulting in, on average, the simultaneous unit recording of upwards of 60 units during a daily recording session. The active electrodes during one recording session tend to remain active in subsequent recording sessions for several weeks. Using the methods described here, implants have been constructed which incorporate several different electrode materials, coatings, sizes, and electrode separation within a single array. These microwire electrode arrays provide the basic technology for obtaining unit recordings for several months. This provides a model system for studying biocompatibility of neural implants, which is a critical component for the development of neural implants that have an indefinite working span.