Behavioral Neuroscience publications

We investigated whether neurons in monkey primary visual cortex (V1) exhibit mixed selectivity for sensory input and behavioral choice. Parallel multisite spiking activity was recorded from area V1 of awake monkeys performing a delayed match-to-sample task. The monkeys had to make a forced choice decision of whether the test stimulus matched the preceding sample stimulus. The population responses evoked by the test stimulus contained information about both the identity of the stimulus and with some delay but before the onset of the motor response the forthcoming choice. The results of subspace identification analysis indicate that stimulus-specific and decision-related information coexists in separate subspaces of the high-dimensional population activity, and latency considerations suggest that the decision-related information is conveyed by top-down projections.

In order to investigate the involvement of primary visual cortex (V1) in working memory (WM), parallel, multisite recordings of multiunit activity were obtained from monkey V1 while the animals performed a delayed match-to-sample (DMS) task. During the delay period, V1 population firing rate vectors maintained a lingering trace of the sample stimulus that could be reactivated by intervening impulse stimuli that enhanced neuronal firing. This fading trace of the sample did not require active engagement of the monkeys in the DMS task and likely reflects the intrinsic dynamics of recurrent cortical networks in lower visual areas. This renders an active, attention-dependent involvement of V1 in the maintenance of working memory contents unlikely. By contrast, population responses to the test stimulus depended on the probabilistic contingencies between sample and test stimuli. Responses to tests that matched expectations were reduced which agrees with concepts of predictive coding.

Social learning (SL) through experience with conspecifics can facilitate the acquisition of many behaviors. Thus, when Mongolian gerbils are exposed to a demonstrator performing an auditory discrimination task, their subsequent task acquisition is facilitated, even in the absence of visual cues. Here, we show that transient inactivation of auditory cortex (AC) during exposure caused a significant delay in task acquisition during the subsequent practice phase, suggesting that AC activity is necessary for SL. Moreover, social exposure induced an improvement in AC neuron sensitivity to auditory task cues. The magnitude of neural change during exposure correlated with task acquisition during practice. In contrast, exposure to only auditory task cues led to poorer neurometric and behavioral outcomes. Finally, social information during exposure was encoded in the AC of observer animals. Together, our results suggest that auditory SL is supported by AC neuron plasticity occurring during social exposure and prior to behavioral performance.

The process by which sensory evidence contributes to perceptual choices requires an understanding of its transformation into decision variables. Here, we address this issue by evaluating the neural representation of acoustic information in the auditory cortex-recipient parietal cortex, while gerbils either performed a two-alternative forced-choice auditory discrimination task or while they passively listened to identical acoustic stimuli. During task engagement, stimulus identity decoding performance from simultaneously recorded parietal neurons significantly correlated with psychometric sensitivity. In contrast, decoding performance during passive listening was significantly reduced. Principal component and geometric analyses revealed the emergence of low-dimensional encoding of linearly separable manifolds with respect to stimulus identity and decision, but only during task engagement. These findings confirm that the parietal cortex mediates a transition of acoustic representations into decision-related variables. Finally, using a clustering analysis, we identified three functionally distinct subpopulations of neurons that each encoded task-relevant information during separate temporal segments of a trial. Taken together, our findings demonstrate how parietal cortex neurons integrate and transform encoded auditory information to guide sound-driven perceptual decisions.

Systems consolidation—a process for long-term memory stabilization—has been hypothesized to occur in two stages 1–4 . Whereas new memories require the hippocampus 5–9 , they become integrated into cortical networks over time 10–12 , making them independent of the hippocampus. How hippocampal–cortical dialogue precisely evolves during this and how cortical representations change in concert is unknown. Here, we use a skill learning task 13,14 to monitor the dynamics of cross-area coupling during non-rapid eye movement sleep along with changes in primary motor cortex (M1) representational stability. Our results indicate that precise cross-area coupling between hippocampus, prefrontal cortex and M1 can demarcate two distinct stages of processing. We specifically find that each animal demonstrates a sharp increase in prefrontal cortex and M1 sleep slow oscillation coupling with stabilization of performance. This sharp increase then predicts a drop in hippocampal sharp-wave ripple (SWR)–M1 slow oscillation coupling—suggesting feedback to inform hippocampal disengagement and transition to a second stage. Notably, the first stage shows significant increases in hippocampal SWR–M1 slow oscillation coupling in the post-training sleep and is closely associated with rapid learning and variability of the M1 low-dimensional manifold. Strikingly, even after consolidation, inducing new manifold exploration by changing task parameters re-engages hippocampal–M1 coupling. We thus find evidence for dynamic hippocampal–cortical dialogue associated with manifold exploration during learning and adaptation.

Animal research focused on chronic tinnitus associated with noise-induced hearing loss can be expensive and time-consuming as a result of the behavioral training required. Although there exist a number of behavioral tests for tinnitus; there have been few formal direct comparisons of these tests. Here, we evaluated animals in two different tinnitus assessment methods. CBA/CaJ mice were trained in an operant conditioning, active avoidance (AA) test, and a reflexive, gap-induced pre-pulse inhibition of acoustic startle (GPIAS) test, or both. Tinnitus was induced in awake mice by unilateral continuous sound exposure using a 2-kHz- or 1 2 octave-wide noise centered at 16 kHz and presented at 113- or 116-dB SPL. Tinnitus was assessed 8 weeks after sound overexposure. Most mice had evidence of tinnitus behavior in at least one of the two behaviors. Of the mice evaluated in AA, over half (55%) had tinnitus positive behavior. In GPIAS, fewer animals (13%) were positive than were identified using the AA test. Few mice were positive in both tests (10%), and only one was positive for tinnitus behavior at the same spectral frequency in both tests. When the association between tinnitus behavior and spontaneous activity recorded in the inferior colliculus was compared, animals with tinnitus behavior in AA exhibited increased spontaneous activity, while those positive in GPIAS did not. Thus, it appears that operant conditioning tests, like AA, maybe more reliable and accurate tests for tinnitus than reflexive tests.

Intracortical microstimulation (ICMS) of the somatosensory cortex (S1) can restore sensory function in patients with paralysis. Studies assessing the stability of ICMS have reported heterogeneous responses across electrodes and over time, potentially hindering the implementation and translatability of these technologies. The foreign body response (FBR) and the encapsulating glial scar have been associated with a decay in chronic performance of implanted electrodes. Moreover, the morphology, intrinsic properties, and function of cells vary across cortical layers, each potentially affecting the sensitivity to ICMS as well as the degree of the FBR across cortical depth. However, layer-by-layer comparisons of the long-term stability of ICMS as well as the extent of the astrocytic glial scar change across cortical layers have not been well explored. Here, we implanted silicon microelectrodes with electrode sites spanning all the layers of S1 in rats. Using a behavioral paradigm, we obtained ICMS detection thresholds from all cortical layers for up to 40 weeks. Our results showed that the sensitivity and long-term performance of ICMS is indeed layer dependent. Overall, detection thresholds decreased during the first 7 weeks post-implantation (WPI). This was followed by a period in which thresholds remained stable or increased depending on the interfacing layer: thresholds in L1 and L6 exhibited the most consistent increases over time, while those in L4 and L5 remained the most stable. Furthermore, histological investigation of the tissue surrounding the electrode showed a biological response of microglia and macrophages which peaked at L1, while the area of the astrocytic glial scar peaked at L2/3. Interestingly, the biological response of these FBR markers is less exacerbated at L4 and L5, suggesting a potential link between the FBR and the long-term stability of ICMS. These findings suggest that interfacing depth can play an important role in the design of chronically stable implantable microelectrodes.

Elevated neural plasticity during development contributes to dramatic improvements in perceptual, motor, and cognitive skills. However, malleable neural circuits are vulnerable to environmental influences that may disrupt behavioral maturation. While these risks are well-established prior to sexual maturity (i.e., critical periods), the degree of neural vulnerability during adolescence remains uncertain. Here, we induce transient hearing loss (HL) spanning adolescence in gerbils, and ask whether behavioral and neural maturation are disrupted. We find that adolescent HL causes a significant perceptual deficit that can be attributed to degraded auditory cortex processing, as assessed with wireless single neuron recordings and within-session population-level analyses. Finally, auditory cortex brain slices from adolescent HL animals reveal synaptic deficits that are distinct from those typically observed after critical period deprivation. Taken together, these results show that diminished adolescent sensory experience can cause long-lasting behavioral deficits that originate, in part, from a dysfunctional cortical circuit.

How memory is organized in cell ensembles when an event is repeated is not well-understood. Recently, we found that retraining 24 h after the initial fear conditioning (FC) event induces turnover of neurons in the lateral amygdala (LA) that encodes fear memory. Excitability-dependent competition between eligible neurons has been suggested as a rule that governs memory allocation. However, it remains undetermined whether excitability is also involved in the allocation of a repeated event. By increasing excitability in a subset of neurons in the LA before FC, we confirmed that these neurons preferentially participated in encoding fear memory as previously reported. These neurons, however, became unnecessary for memory recall after retraining 24 h following initial FC. Consistently, the initial memory-encoding neurons became less likely to be reactivated during recall. This reorganization in cell ensembles, however, was not induced and memory was co-allocated when retraining occurred 6 h after the initial FC. In 24-h retraining condition, artificially increasing excitability right before retraining failed to drive memory co-allocation. These results suggest a distinct memory allocation mechanism for repeated events distantly separated in time.

Background To localize sound sources accurately in a reverberant environment, human binaural hearing strongly favors analyzing the initial wave front of sounds. Behavioral studies of this “precedence effect” have so far largely been confined to human subjects, limiting the scope of complementary physiological approaches. Similarly, physiological studies have mostly looked at neural responses in the inferior colliculus, the main relay point between the inner ear and the auditory cortex, or used modeling of cochlear auditory transduction in an attempt to identify likely underlying mechanisms. Studies capable of providing a direct comparison of neural coding and behavioral measures of sound localization under the precedence effect are lacking. Results We adapted a “temporal weighting function” paradigm previously developed to quantify the precedence effect in human for use in laboratory rats. The animals learned to lateralize click trains in which each click in the train had a different interaural time difference. Computing the “perceptual weight” of each click in the train revealed a strong onset bias, very similar to that reported for humans. Follow-on electrocorticographic recording experiments revealed that onset weighting of interaural time differences is a robust feature of the cortical population response, but interestingly, it often fails to manifest at individual cortical recording sites. Conclusion While previous studies suggested that the precedence effect may be caused by early processing mechanisms in the cochlea or inhibitory circuitry in the brainstem and midbrain, our results indicate that the precedence effect is not fully developed at the level of individual recording sites in the auditory cortex, but robust and consistent precedence effects are observable only in the auditory cortex at the level of cortical population responses. This indicates that the precedence effect emerges at later cortical processing stages and is a significantly “higher order” feature than has hitherto been assumed.

Cognitive operations are widely studied by measuring electric fields through EEG and ECoG. However, despite their widespread use, the neural circuitry giving rise to these signals remains unknown because the functional architecture of cortical columns producing attention-associated electric fields has not been explored. Here, we detail the laminar cortical circuitry underlying an attention-associated electric field measured over posterior regions of the brain in humans and monkeys. First, we identified visual cortical area V4 as one plausible contributor to this attention-associated electric field through inverse modeling of cranial EEG in macaque monkeys performing a visual attention task. Next, we performed laminar neurophysiological recordings on the prelunate gyrus and identified the electric-field-producing dipoles as synaptic activity in distinct cortical layers of area V4. Specifically, activation in the extragranular layers of cortex resulted in the generation of the attention-associated dipole. Feature selectivity of a given cortical column determined the overall contribution to this electric field. Columns selective for the attended feature contributed more to the electric field than columns selective for a different feature. Last, the laminar profile of synaptic activity generated by V4 was sufficient to produce an attention-associated signal measurable outside of the column. These findings suggest that the top-down recipient cortical layers produce an attention-associated electric field that can be measured extracortically with the relative contribution of each column depending upon the underlying functional architecture.

Dysregulated homeostasis of neural activity has been hypothesized to drive Alzheimer's disease (AD) pathogenesis. AD begins with a decades-long presymptomatic phase, but whether homeostatic mechanisms already begin failing during this silent phase is unknown. We show that before the onset of memory decline and sleep disturbances, familial AD (fAD) model mice display no deficits in CA1 mean firing rate (MFR) during active wakefulness. However, homeostatic down-regulation of CA1 MFR is disrupted during non-rapid eye movement (NREM) sleep and general anesthesia in fAD mouse models. The resultant hyperexcitability is attenuated by the mitochondrial dihydroorotate dehydrogenase (DHODH) enzyme inhibitor, which tunes MFR toward lower set-point values. Ex vivo fAD mutations impair downward MFR homeostasis, resulting in pathological MFR set points in response to anesthetic drug and inhibition blockade. Thus, firing rate dyshomeostasis of hippocampal circuits is masked during active wakefulness but surfaces during low-arousal brain states, representing an early failure of the silent disease stage.

Previous psychophysical studies have identified a hierarchy of time-averaged statistics which determine the identity of natural sound textures. However, it is unclear whether the neurons in the inferior colliculus (IC) are sensitive to each of these statistical features in the natural sound textures. We used 13 representative sound textures spanning the space of 3 statistics extracted from over 200 natural textures. The synthetic textures were generated by incorporating the statistical features in a step-by-step manner, in which a particular statistical feature was changed while the other statistical features remain unchanged. The extracellular activity in response to the synthetic texture stimuli was recorded in the IC of anesthetized rats. Analysis of the transient and sustained multiunit activity after each transition of statistical feature showed that the IC units were sensitive to the changes of all types of statistics, although to a varying extent. For example, we found that more neurons were sensitive to the changes in variance than that in the modulation correlations. Our results suggest that the sensitivity of the statistical features in the subcortical levels contributes to the identification and discrimination of natural sound textures.

Although fear memory formation is essential for survival and fear-related mental disorders, the neural circuitry and mechanism are incompletely understood. Here, we utilized trace fear conditioning to study the formation of trace fear memory in mice. We identified the entorhinal cortex (EC) as a critical component of sensory signaling to the amygdala. We adopted both loss-of-function and gain-of-function experiments to demonstrate that release of the cholecystokinin (CCK) from the EC is required for trace fear memory formation. We discovered that CCK-positive neurons project from the EC to the lateral nuclei of the amygdala (LA), and inhibition of CCK-dependent signaling in the EC prevented long-term potentiation of the auditory response in the LA and formation of trace fear memory. In summary, high-frequency activation of EC neurons triggers the release of CCK in their projection terminals in the LA, potentiating auditory response in LA neurons. The neural plasticity in the LA leads to trace fear memory formation.

Slow waves and cognitive output have been modulated in humans by phase-targeted auditory stimulation. However, to advance its technical development and further our understanding, implementation of the method in animal models is indispensable. Here, we report the successful employment of slow waves’ phase-targeted closed-loop auditory stimulation (CLAS) in rats. To validate this new tool both conceptually and functionally, we tested the effects of up- and down-phase CLAS on proportions and spectral characteristics of sleep, and on learning performance in the single-pellet reaching task, respectively. Without affecting 24 hr sleep-wake behavior, CLAS specifically altered delta (slow waves) and sigma (sleep spindles) power persistently over chronic periods of stimulation. While up-phase CLAS does not elicit a significant change in behavioral performance, down-phase CLAS exerted a detrimental effect on overall engagement and success rate in the behavioral test. Overall CLAS-dependent spectral changes were positively correlated with learning performance. Altogether, our results provide proof-of-principle evidence that phase-targeted CLAS of slow waves in rodents is efficient, safe, and stable over chronic experimental periods, enabling the use of this high-specificity tool for basic and preclinical translational sleep research.

Memory is supported by a specific collection of neurons distributed in broad brain areas, an engram. Despite recent advances in identifying an engram, how the engram is created during memory formation remains elusive. To explore the relation between a specific pattern of input activity and memory allocation, here we target a sparse subset of neurons in the auditory cortex and thalamus. The synaptic inputs from these neurons to the lateral amygdala (LA) are not potentiated by fear conditioning. Using an optogenetic priming stimulus, we manipulate these synapses to be potentiated by the learning. In this condition, fear memory is preferentially encoded in the manipulated cell ensembles. This change, however, is abolished with optical long-term depression (LTD) delivered shortly after training. Conversely, delivering optical long-term potentiation (LTP) alone shortly after fear conditioning is sufficient to induce the preferential memory encoding. These results suggest a synaptic plasticity-dependent competition rule underlying memory formation.

Development is a time of great opportunity. A heightened period of neural plasticity contributes to dramatic improvements in perceptual, motor, and cognitive skills. However, developmental plasticity poses a risk: greater malleability of neural circuits exposes them to environmental factors that may impede behavioral maturation. While these risks are well-established prior to sexual maturity (i.e., critical periods), the degree of neural vulnerability during adolescence remains uncertain. To address this question, we induced a transient period of hearing loss (HL) spanning adolescence in the gerbil, confirmed by assessment of circulating sex hormones, and asked whether behavioral and neural deficits are diminished. Wireless recordings were obtained from auditory cortex neurons during perceptual task performance, and within-session behavioral and neural sensitivity were compared. We found that a transient period of adolescent HL caused a significant perceptual deficit (i.e., amplitude modulation detection thresholds) that could be attributed to degraded auditory cortex processing, as confirmed with both single neuron and population-level analyses. In contrast, perceptual deficits did not occur when HL of the same duration was induced in adulthood. To determine whether degraded auditory cortex encoding was attributable to an intrinsic change, we obtained auditory cortex brain slices from adolescent HL animals, and recorded synaptic and discharge properties from auditory cortex pyramidal neurons. There was a clear and novel phenotype, distinct from critical period HL: excitatory postsynaptic potential amplitudes were elevated in adolescent HL animals, whereas inhibitory postsynaptic potentials were unchanged. This is in contrast to critical period deprivation, where there are large changes to synaptic inhibition. Taken together, these results show that diminished adolescent sensory experience can cause long-lasting behavioral deficits that originate, in part, from a dysfunctional cortical circuit. Abstract Figure Summary of experimental design and main findings.

Recent studies have shown that rats are a useful model for binaural cochlear implant (CI) research, with behavioral sensitivity to interaural time differences (ITDs) of CI stimuli which are better than those of human patients. Here, we characterize ITD tuning in the rat inferior colliculus (IC) and explore whether quality of tuning can predict behavioral performance. We recorded IC responses to stimuli of varying pulse rates and envelope types and quantified both mutual information (MI) and neural d ′ as measures of ITD sensitivity. Neural d ′ values paralleled behavioral ones, declining with increasing click rates or when envelopes changed from rectangular to Hanning windows. While MI values increased with experience, neural d ′ did not. However, neural d ′ values correlated much better with behavioral performance than MI. Thus, neural d ′ appears to be a particularly well suited to predicting how stimulus parameters will impact behavioral performance.

Continuous acoustic streams, such as speech signals, can be chunked into segments containing reoccurring patterns (e.g., words). Noninvasive recordings of neural activity in humans suggest that chunking is underpinned by low-frequency cortical entrainment to the segment presentation rate, and modulated by prior segment experience (e.g., words belonging to a familiar language). Interestingly, previous studies suggest that also primates and rodents may be able to chunk acoustic streams. Here, we test whether neural activity in the rat auditory cortex is modulated by previous segment experience. We recorded subdural responses using electrocorticography (ECoG) from the auditory cortex of 11 anesthetized rats. Prior to recording, four rats were trained to detect familiar triplets of acoustic stimuli (artificial syllables), three were passively exposed to the triplets, while another four rats had no training experience. While low-frequency neural activity peaks were observed at the syllable level, no triplet-rate peaks were observed. Notably, in trained rats (but not in passively exposed and naïve rats), familiar triplets could be decoded more accurately than unfamiliar triplets based on neural activity in the auditory cortex. These results suggest that rats process acoustic sequences, and that their cortical activity is modulated by the training experience even under subsequent anesthesia.

As we navigate in space, external landmarks and internal information guide our movement. Circuit and synaptic mechanisms that integrate these cues with head-direction (HD) signals remain, however, unclear. We identify an excitatory synaptic projection from the presubiculum (PreS) and the multisensory-associative retrosplenial cortex (RSC) to the anterodorsal thalamic reticular nucleus (TRN), so far classically implied in gating sensory information flow. In vitro, projections to TRN involve AMPA/NMDA-type glutamate receptors that initiate TRN cell burst discharge and feedforward inhibition of anterior thalamic nuclei. In vivo, chemogenetic anterodorsal TRN inhibition modulates PreS/RSC-induced anterior thalamic firing dynamics, broadens the tuning of thalamic HD cells, and leads to preferential use of allo- over egocentric search strategies in the Morris water maze. TRN-dependent thalamic inhibition is thus an integral part of limbic navigational circuits wherein it coordinates external sensory and internal HD signals to regulate the choice of search strategies during spatial navigation.