RESUMO
Excitatory and inhibitory neurons in the mammalian sensory cortex form interconnected circuits that control cortical stimulus selectivity and sensory acuity. Theoretical studies have predicted that suppression of inhibition in such excitatory-inhibitory networks can lead to either an increase or, paradoxically, a decrease in excitatory neuronal firing, with consequent effects on stimulus selectivity. We tested whether modulation of inhibition or excitation in the auditory cortex of male mice could evoke such a variety of effects in tone-evoked responses and in behavioral frequency discrimination acuity. We found that, indeed, the effects of optogenetic manipulation on stimulus selectivity and behavior varied in both magnitude and sign across subjects, possibly reflecting differences in circuitry or expression of optogenetic factors. Changes in neural population responses consistently predicted behavioral changes for individuals separately, including improvement and impairment in acuity. This correlation between cortical and behavioral change demonstrates that, despite the complex and varied effects that these manipulations can have on neuronal dynamics, the resulting changes in cortical activity account for accompanying changes in behavioral acuity.SIGNIFICANCE STATEMENT Excitatory and inhibitory interactions determine stimulus specificity and tuning in sensory cortex, thereby controlling perceptual discrimination acuity. Modeling has predicted that suppressing the activity of inhibitory neurons can lead to increased or, paradoxically, decreased excitatory activity depending on the architecture of the network. Here, we capitalized on differences between subjects to test whether suppressing/activating inhibition and excitation can in fact exhibit such paradoxical effects for both stimulus sensitivity and behavioral discriminability. Indeed, the same optogenetic manipulation in the auditory cortex of different mice could improve or impair frequency discrimination acuity, predictable from the effects on cortical responses to tones. The same manipulations sometimes produced opposite changes in the behavior of different individuals, supporting theoretical predictions for inhibition-stabilized networks.
Assuntos
Córtex Auditivo/fisiologia , Simulação por Computador , Modelos Neurológicos , Inibição Neural/fisiologia , Neurônios/fisiologia , Estimulação Acústica , Animais , Percepção Auditiva/fisiologia , Potenciais Evocados Auditivos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , OptogenéticaRESUMO
The ability to discriminate tones of different frequencies is fundamentally important for everyday hearing. While neurons in the primary auditory cortex (AC) respond differentially to tones of different frequencies, whether and how AC regulates auditory behaviors that rely on frequency discrimination remains poorly understood. Here, we find that the level of activity of inhibitory neurons in AC controls frequency specificity in innate and learned auditory behaviors that rely on frequency discrimination. Photoactivation of parvalbumin-positive interneurons (PVs) improved the ability of the mouse to detect a shift in tone frequency, whereas photosuppression of PVs impaired the performance. Furthermore, photosuppression of PVs during discriminative auditory fear conditioning increased generalization of conditioned response across tone frequencies, whereas PV photoactivation preserved normal specificity of learning. The observed changes in behavioral performance were correlated with bidirectional changes in the magnitude of tone-evoked responses, consistent with predictions of a model of a coupled excitatory-inhibitory cortical network. Direct photoactivation of excitatory neurons, which did not change tone-evoked response magnitude, did not affect behavioral performance in either task. Our results identify a new function for inhibition in the auditory cortex, demonstrating that it can improve or impair acuity of innate and learned auditory behaviors that rely on frequency discrimination.
Assuntos
Córtex Auditivo/fisiologia , Comportamento Animal , Aprendizagem por Discriminação , Generalização da Resposta , Instinto , Interneurônios/fisiologia , Modelos Neurológicos , Estimulação Acústica , Animais , Córtex Auditivo/efeitos da radiação , Comportamento Animal/efeitos da radiação , Biomarcadores/metabolismo , Condicionamento Clássico , Condicionamento Operante , Aprendizagem por Discriminação/efeitos da radiação , Generalização da Resposta/efeitos da radiação , Interneurônios/efeitos da radiação , Luz , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Parvalbuminas/genética , Parvalbuminas/metabolismo , Proteínas Recombinantes de Fusão/metabolismoRESUMO
The larval zebrafish is a model organism to study the neural circuitry underlying behavior. There exist, however, few examples of robust long-term memory. Here we describe a simple, unrestrained associative place-conditioning paradigm. We show that visual access to a group of conspecifics has rewarding properties for 6- to 8-day-old larval zebrafish. We use this social reward as an unconditioned stimulus and pair it with a distinct visual environment. After training, larvae exhibited spatial preference for the location previously paired with the social reward for up to 36 h, indicating that zebrafish larvae can exhibit long-term associative memory. Furthermore, incubation with a protein synthesis inhibitor or an NMDAR-antagonist impaired memory. In future experiments, this learning paradigm could be used to study the social interactions of larval zebrafish or paired with cell-specific metabolic labeling to visualize circuits underlying memory formation.
Assuntos
Antagonistas de Aminoácidos Excitatórios/farmacologia , Memória de Longo Prazo/efeitos dos fármacos , Inibidores da Síntese de Proteínas/farmacologia , Animais , Condicionamento Clássico/efeitos dos fármacos , Larva , Biossíntese de Proteínas , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Recompensa , Peixe-ZebraRESUMO
Understanding how neuronal network activity contributes to memory formation is challenged by the complexity of most brain circuits and the restricted ability to monitor the activity of neuronal populations in vivo. The developing zebrafish (Danio rerio) is an animal model that circumvents these problems, because zebrafish larvae possess a rich behavioral repertoire and an accessible brain. Here, we developed a classical conditioning paradigm in which 6- to 8-d-old larvae develop an enhanced motor response to a visual stimulus (conditioned stimulus, CS) when it is paired with touch (unconditioned stimulus, US). Using in vivo calcium imaging we demonstrate that CS and US activate different subsets of neurons in the cerebellum; their activity, modulated by learning two-photon laser ablation, revealed that the cerebellum is involved in acquisition and extinction, but not the retention, of this memory.
Assuntos
Cerebelo/fisiologia , Condicionamento Clássico/fisiologia , Larva/fisiologia , Peixe-Zebra/fisiologia , Análise de Variância , Animais , Cerebelo/citologia , Cerebelo/cirurgia , Ácido Egtázico/análogos & derivados , Lateralidade Funcional , Terapia a Laser/métodos , Locomoção , Neurônios/classificação , Neurônios/fisiologia , Estimulação Luminosa , Estatísticas não Paramétricas , TatoRESUMO
Many forms of behavior require selective amplification of neuronal representations of relevant environmental signals. Emotional learning enhances sensory responses in the sensory cortex, yet the underlying circuits remain poorly understood. We identify a pathway between the basolateral amygdala (BLA), an emotional learning center in the mouse brain, and the inhibitory reticular nucleus of the thalamus (TRN). Optogenetic activation of BLA suppressed spontaneous, but not tone-evoked, activity in the auditory cortex (AC), amplifying tone-evoked responses. Viral tracing identified BLA projections terminating at TRN. Optogenetic activation of amygdala-TRN projections further amplified tone-evoked responses in the auditory thalamus and cortex. The results are explained by a computational model of the thalamocortical circuitry, in which activation of TRN by BLA primes thalamocortical neurons to relay relevant sensory input. This circuit mechanism shines a neural spotlight on behaviorally relevant signals and provides a potential target for the treatment of neuropsychological disorders.
Assuntos
Tonsila do Cerebelo/fisiologia , Potenciais Evocados Auditivos , Núcleos Talâmicos/fisiologia , Tonsila do Cerebelo/citologia , Animais , Córtex Auditivo/citologia , Córtex Auditivo/fisiologia , Percepção Auditiva , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Núcleos Talâmicos/citologiaRESUMO
Tinnitus is an auditory disorder, which affects millions of Americans, including active duty service members and veterans. It is manifested by a phantom sound that is commonly restricted to a specific frequency range. Because tinnitus is associated with hearing deficits, understanding how tinnitus affects hearing perception is important for guiding therapies to improve the quality of life in this vast group of patients. In a rodent model of tinnitus, prolonged exposure to a tone leads to a selective decrease in gap detection in specific frequency bands. However, whether and how hearing acuity is affected for sounds within and outside those frequency bands is not well understood. We induced tinnitus in mice by prolonged exposure to a loud mid-range tone, and behaviorally assayed whether mice exhibited a change in frequency discrimination acuity for tones embedded within the mid-frequency range and high-frequency range at 1, 4, and 8 weeks post-exposure. A subset of tone-exposed mice exhibited tinnitus-like symptoms, as demonstrated by selective deficits in gap detection, which were restricted to the high frequency range. These mice exhibited impaired frequency discrimination both for tones in the mid-frequency range and high-frequency range. The remaining tone exposed mice, which did not demonstrate behavioral evidence of tinnitus, showed temporary deficits in frequency discrimination for tones in the mid-frequency range, while control mice remained unimpaired. Our findings reveal that the high frequency-specific deficits in gap detection, indicative of tinnitus, are associated with impairments in frequency discrimination at the frequency of the presumed tinnitus.
Assuntos
Perda Auditiva/fisiopatologia , Percepção Sonora , Zumbido/fisiopatologia , Animais , Audiometria de Tons Puros , Modelos Animais de Doenças , Perda Auditiva/etiologia , Humanos , Masculino , Camundongos , Som , Zumbido/etiologiaRESUMO
Reliably detecting unexpected sounds is important for environmental awareness and survival. By selectively reducing responses to frequently, but not rarely, occurring sounds, auditory cortical neurons are thought to enhance the brain's ability to detect unexpected events through stimulus-specific adaptation (SSA). The majority of neurons in the primary auditory cortex exhibit SSA, yet little is known about the underlying cortical circuits. We found that two types of cortical interneurons differentially amplify SSA in putative excitatory neurons. Parvalbumin-positive interneurons (PVs) amplify SSA by providing non-specific inhibition: optogenetic suppression of PVs led to an equal increase in responses to frequent and rare tones. In contrast, somatostatin-positive interneurons (SOMs) selectively reduce excitatory responses to frequent tones: suppression of SOMs led to an increase in responses to frequent, but not to rare tones. A mutually coupled excitatory-inhibitory network model accounts for distinct mechanisms by which cortical inhibitory neurons enhance the brain's sensitivity to unexpected sounds.
Assuntos
Adaptação Fisiológica , Córtex Auditivo/fisiologia , Interneurônios/fisiologia , Som , Estimulação AcústicaRESUMO
Although emotional learning affects sensory acuity, little is known about how these changes are facilitated in the brain. We found that auditory fear conditioning in mice elicited either an increase or a decrease in frequency discrimination acuity depending on how specific the learned response was to the conditioned tone. Using reversible pharmacological inactivation, we found that the auditory cortex mediated learning-evoked changes in acuity in both directions.